Pyridazinones as parp7 inhibitors

ABSTRACT

The present invention relates to pyridazinones and related compounds which are inhibitors of PARP7 and are useful in the treatment of cancer.

CLAIM OF PRIORITY

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 62/664,544, filed on Apr. 30, 2018, the entire contents ofwhich are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to pyridazinones and related compoundswhich are inhibitors of PARP7 and are useful in the treatment of cancer.

BACKGROUND OF THE INVENTION

Poly(ADP-ribose) polymerases (PARPs) are members of a family ofseventeen enzymes that regulate fundamental cellular processes includinggene expression, protein degradation, and multiple cellular stressresponses (M. S. Cohen, P. Chang, Insights into the biogenesis,function, and regulation of ADP-ribosylation. Nat Chem Biol 14, 236-243(2018)). The ability of cancer cells to survive under stress is afundamental cancer mechanism and an emerging approach for noveltherapeutics. One member of the PARP family, PARP1, has already beenshown to be an effective cancer target in connection to cellular stressinduced by DNA damage, either induced by genetic mutation or withcytotoxic chemotherapy, with three approved drugs in the clinic andseveral others in late stage development (A. Ohmoto, S. Yachida, Currentstatus of poly(ADP-ribose) polymerase inhibitors and future directions.Onco Targets Ther 10, 5195-5208 (2017)).

The seventeen members of the PARP family were identified in the humangenome based on the homology within their catalytic domains (S. Vyas, M.Chesarone-Cataldo, T. Todorova, Y. H. Huang, P. Chang, A systematicanalysis of the PARP protein family identifies new functions criticalfor cell physiology. Nat Commun 4, 2240 (2013)). However, theircatalytic activities fall into 3 different categories (S. Vyas et al.,Family-wide analysis of poly(ADP-ribose) polymerase activity. Nat Commun5, 4426 (2014)). The majority of PARP family members catalyze thetransfer of mono-ADP-ribose units onto their substrates (monoPARPs),while others (PARP1, PARP2, TNKS, TNKS2) catalyze the transfer ofpoly-ADP-ribose units onto substrates (polyPARPs). Finally, PARP13 isthus far the only PARP for which catalytic activity could not bedemonstrated either in vitro or in vivo.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcriptionfactor involved in regulating multiple cellular functions includingproinflammatory responses and xenobiotic metabolism (S. Feng, Z. Cao, X.Wang, Role of aryl hydrocarbon receptor in cancer. Biochim Biophys Acta1836, 197-210 (2013); and B. Stockinger, P. Di Meglio, M. Gialitakis, J.H. Duarte, The aryl hydrocarbon receptor: multitasking in the immunesystem. Annu Rev Immunol 32, 403-432 (2014)). The AHR can be activatedby a broad number of ligands including endogenous tryptophan metabolitessuch as kynurenine (C. A. Opitz et al., An endogenous tumour-promotingligand of the human aryl hydrocarbon receptor. Nature 478, 197-203(2011)) and certain polycyclic aromatic hydrocarbons such as2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (K. W. Bock, Towardelucidation of dioxin-mediated chloracne and Ah receptor functions.Biochem Pharmacol 112, 1-5 (2016)). Activation of the AHR induces targetgene expression including genes involved in metabolism such ascytochrome P4501A1 and P4501B1. Activation of AHR also leads to anincrease in the AHR target gene, TCDD-induciblepoly(ADP-ribose)polymerase (TIPARP, also referred to as PARP7), whichfunctions as a negative regulator of certain AHR transcriptional targets(L. MacPherson et al., Aryl hydrocarbon receptor repressor and TIPARP(ARTD14) use similar, but also distinct mechanisms to repress arylhydrocarbon receptor signaling. Int J Mot Sci 15, 7939-7957 (2014); andL. MacPherson et al., 2,3,7,8-Tetrachlorodibenzo-p-dioxinpoly(ADP-ribose) polymerase (TIPARP, ARTD14) is amono-ADP-ribosyltransferase and repressor of aryl hydrocarbon receptortransactivation. Nucleic Acids Res 41, 1604-1621 (2013)).

PARP7 can also be regulated by other transcription factors and signalingpathways including androgen receptor (E. C. Bolton et al., Cell- andgene-specific regulation of primary target genes by the androgenreceptor. Genes Dev 21, 2005-2017 (2007)), platelet derived growthfactor (J. Schmahl, C. S. Raymond, P. Soriano, PDGF signalingspecificity is mediated through multiple immediate early genes. NatGenet 39, 52-60 (2007)) and hypoxia inducible factor 1 (N. Hao et al.,Xenobiotics and loss of cell adhesion drive distinct transcriptionaloutcomes by aryl hydrocarbon receptor signaling. Mot Pharmacol 82,1082-1093 (2012)). The PARP7 gene is located on chromosome 3 (3q25) in aregion that is frequently amplified in cancers of squamous histology(http://www.cbioportal.org/index.do?session_id=5ae1bcde498eb8b3d565d8b2).A genome-wide association study identified 3q25 as susceptibility locifor ovarian cancer suggesting a role for PARP7 in this cancer type (E.L. Goode et al., A genome-wide association study identifiessusceptibility loci for ovarian cancer at 2q31 and 8q24. Nat Genet 42,874-879 (2010)). PARP7 has multiple cellular functions. In the contextof AHR signaling PARP7 acts as a negative feedback mechanism to regulatethe expression of P4501A1 and P4501B1 (L. MacPherson et al., Arylhydrocarbon receptor repressor and TIPARP (ARTD14) use similar, but alsodistinct mechanisms to repress aryl hydrocarbon receptor signaling. IntJ Mot Sci 15, 7939-7957 (2014), and L. MacPherson et al.,2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase (TIPARP,ARTD14) is a mono-ADP-ribosyltransferase and repressor of arylhydrocarbon receptor transactivation. Nucleic Acids Res 41, 1604-1621(2013)). PARP7 has also been described to ADP-ribosylate liver Xreceptors which leads to the modulation of their transcriptionalactivity (C. Bindesboll et al., TCDD-inducible poly-ADP-ribosepolymerase (TIPARP/PARP7) mono-ADP-ribosylates and co-activates liver Xreceptors. Biochem J 473, 899-910 (2016). During viral infection PARP7can bind to Sindbis virus (SINV) to promote viral RNA degradation (T.Kozaki et al., Mitochondrial damage elicits a TCDD-induciblepoly(ADP-ribose) polymerase-mediated antiviral response. Proc Natl AcadSci USA 114, 2681-2686 (2017)). Also in the context of viral infection,AHR-induced PARP7 can interact with TBK1, a major kinase that isactivated during the onset of pathogen-associated molecular patternpathways leading to an activation of the Type I interferon response andantiviral immunity (T. Yamada et al., Constitutive aryl hydrocarbonreceptor signaling constrains Type I interferon-mediated antiviralinnate defense. Nat Immunol 17, 687-694 (2016)). PARP7 was shown toADP-ribosylate TBK1 which prevents its activation, thereby repressingthe Type I interferon response.

Based on these results from viral infection one could hypothesize thatcancer cells can use aberrantly expressed and/or activated PARP7 as amechanism to evade the host immune system through suppression of theType I interferons and thereby T cell mediated antitumor immunity.Indeed, in a recent genetic screen to identify tumor factors thatsuppress T cell activation PARP7 was identified as a hit (D. Pan et al.,A major chromatin regulator determines resistance of tumor cells to Tcell-mediated killing. Science 359, 770-775 (2018)). PARP7 knockout in amouse melanoma cell line was shown to increase the proliferation andactivation of co-cultured T cells suggesting that PARP7 inhibition maybe a viable strategy to activate T cell mediated tumor killing.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein constituentmembers are defined below.

The present invention is further directed to a pharmaceuticalcomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier.

The present invention is further directed to a method of inhibiting theactivity of PARP7 comprising contacting a compound of Formula I, or apharmaceutically acceptable salt thereof, with PARP7.

The present invention is further directed to a method of treating adisease or disorder in a patient in need of treatment, where the diseaseor disorder is characterized by overexpression or increased activity ofPARP7, comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof.

The present invention is further directed to a method of treating cancerin a subject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of an agent that inhibitsPARP7 activity, such as a compound of Formula I, or a pharmaceuticallyacceptable salt thereof. The present disclosure also provides uses ofthe compounds described herein in the manufacture of a medicament foruse in therapy. The present disclosure also provides the compoundsdescribed herein for use in therapy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A illustrates PARP7 amplification across TCGA (The Cancer GenomeAtlas) primary tumor samples.

FIG. 1B illustrates that PARP7 copy-number amplifications correspond toincreased levels of PARP7 mRNA expression levels in TCGA (The CancerGenome Atlas) lung squamous tumor samples.

FIG. 2 illustrates the inhibition of cancer cell growth by PARP7inhibitors (compounds of Examples 18B, 39, 98, and 93A), showing adose-dependent decrease in growth of NCI-H1373 lung cancer cells.

FIG. 3 illustrates the induction of interferon-beta (IFN-β) levels byPARP7 inhibitors (compounds of Examples 18B and 98) in CT26 mouse coloncancer cells and RAW264.7 mouse macrophages in the presence of a STINGagonist, DMXAA (also known as Vadimezan or ASA404).

FIG. 4 illustrates the induction of STAT1 phosphorylation by a PARP7inhibitor in CT26 mouse colon cancer cells and RAW264.7 mousemacrophages.

FIG. 5 illustrates proliferation in CT26 cells in vitro in the presenceof PARP7 inhibitor (compound of Example 18B).

FIG. 6A illustrates tumor growth in the murine syngeneic model CT26(control).

FIG. 6B illustrates tumor growth in the murine syngeneic model CT26 inthe presence of the compound of Example 98.

FIG. 6C illustrates tumor growth in the murine syngeneic model CT26 inthe presence of the compound of Example 93A.

FIG. 6D illustrates tumor growth in the murine syngeneic model 4T1(control).

FIG. 6E illustrates tumor growth in the murine syngeneic model 4T1 inthe presence of the compound of Example 98.

FIG. 6F illustrates tumor growth in the murine syngeneic model 4T1 inthe presence of the compound of Example 93A.

FIG. 7A illustrates that once daily administration of the PARP7inhibitor of Example 561 significantly reduces tumor growth in a humanNCI-H1373 lung cancer xenograft.

FIG. 7B illustrates that once or twice daily administration of the PARP7inhibitor of Example 561 significantly reduces tumor growth in a murineCT26 colon cancer syngeneic model.

FIG. 8 shows an X-ray powder diffraction (XRPD) pattern of the compoundof Example 561 Form A.

FIG. 9 shows a differential scanning calorimetry (DSC) andthermogravimetric analysis (TGA) thermogram of the compound of Example561 Form A.

FIG. 10 shows a dynamic vapor sorption (DVS) isotherm of the compound ofExample 561 Form A.

DETAILED DESCRIPTION

The present invention is directed to a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is Cl, Br, CH₃, CF₃, CN, OCH₃, ethyl, cyclopropyl, SCH₃, or isopropyl;

A is a group having a formula selected from (A-1), (A-2), and (A-3):

Y¹, Y², and Y³ are each independently selected from O, S, NR, C(═O),C(═O)O, C(═O)NR^(Y), S(═O), S(═O)₂, S(═O)NR^(Y), S(═O)₂NR^(Y) orNR^(Y)C(═O)NR^(Y), wherein each R^(Y) is independently H or C₁₋₄ alkyl;

L is C₁₋₃ alkylene, O, S, NR^(Y), C(═O), C(═O)O, C(═O)NR^(Y), S(═O),S(═O)NR^(Y), or NR^(Y)C(═O)NR^(Y);

Z is H, Cy^(Z), halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl of Z are each optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from Cy^(Z),halo, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d)S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d);

Cy^(Z) is selected from C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl, each optionallysubstituted by 1, 2, 3, or 4 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1), wherein thealkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionally substituted with 1,2, or 3 substituents independently selected from halo, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

Ring D is a monocyclic or polycyclic 4-10 membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 groups independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2)S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, or 3 groups independently selected from halo, CN, NO₂,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are eachindependently selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl of said R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, and R¹² are each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a3), SR^(a3)C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3);

or R¹ and R³ together with the carbon atoms to which they are attachedform a C₅₋₁₀ cycloalkyl ring or a 5-10 membered heterocycloalkyl ring,each optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3);

or R³ and R⁵ together with the carbon atoms to which they are attachedform a C₅₋₁₀ cycloalkyl ring or a 5-10 membered heterocycloalkyl ring,each optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3) S(O)₂R^(b3),NR^(c3) S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3);

or R⁷ and R⁹ together with the carbon atoms to which they are attachedform a C₅₋₁₀ cycloalkyl ring or a 5-10 membered heterocycloalkyl ring,each optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3);

or R⁹ and R¹¹ together with the carbon atoms to which they are attachedform a C₅₋₁₀ cycloalkyl ring or a 5-10 membered heterocycloalkyl ring,each optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3) S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3);

or R⁵ and R⁷ together with the carbon atoms to which they are attachedand together with Y² form a 5-10 membered heterocycloalkyl ringoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR³C(O)NR^(c3)R^(d3),C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3) S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3);

or R¹ and R³ together form a double bond between the carbon atoms towhich they are attached;

or R³ and R⁵ together form a double bond between the carbon atoms towhich they are attached;

or R⁷ and R⁹ together form a double bond between the carbon atoms towhich they are attached;

or R⁹ and R¹¹ together form a double bond between the carbon atoms towhich they are attached;

or R⁹, R¹⁰, R¹¹, and R¹² together form a triple bond between the carbonatoms to which they are attached;

R¹³, R¹⁴, and R¹⁵ are each independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₇cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, CN,NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl of said R¹³, R¹⁴, and R¹⁵ are eachoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4),C(═NR^(e4))R^(b4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),and S(O)₂NR^(c4)R^(d4);

Ring E is a mono- or polycyclic ring selected from C₆₋₁₀ aryl, C₃₋₇cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl;

Q¹, Q², and Q³ are each a group of formula (B-1):

Y⁴, Y⁵, and Y⁶ are each independently selected from O, S, NR^(Y), C(═O),C(═O)O, C(═O)NR^(Y), S(═O), S(═O)₂, S(═O)NR^(Y), S(═O)₂NR^(Y) orNR^(Y)C(═O)NR^(Y);

G¹ is —C(R^(G))(R^(H))— or a group of formula (C-1), (C-2), or (C-3):

G² is —C(R^(I))(R^(J))— or a group of formula (C-1), (C-2), or (C-3);

R^(A), R^(B), R^(C), R^(D), R^(E), R^(F), R^(G), R^(H), R^(I), R^(J),R^(K), R^(L), R^(M), and R^(N) are each independently selected from H,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,5-10 membered heteroaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄alkyl, CN, NO₂, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), —NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b), and S(O)₂NR^(c5)R^(d5); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₇cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, and 4-10 membered heterocycloalkyl-C₁₋₄ alkyl ofsaid R^(A), R^(B), R^(C), R^(D), R^(E), R^(F), R^(G), R^(H), R^(I),R^(J), R^(K), R^(L), R^(M), and R^(N) are each optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), C(═NR^(e))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);

or R^(G) and R^(I) together with the carbon atoms to which they areattached and together with Y⁵ form a 5-10 membered heterocycloalkyl ringoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR³C(O)NR^(c3)R^(d3),C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3);

or R^(C) and R^(E) together form a double bond between the carbon atomsto which they are attached;

or R^(E) and R^(G) together form a double bond between the carbon atomsto which they are attached;

or R^(I) and R^(K) together form a double bond between the carbon atomsto which they are attached;

or R^(K) and R^(M) together form a double bond between the carbon atomsto which they are attached;

or R^(K), R^(L), R^(M), and R^(N) together form a triple bond betweenthe carbon atoms to which they are attached;

D¹ and D² are each independently selected from N and CH;

D³, D⁴, D⁵, D⁶, D⁷, D⁸, and D⁹ are each independently selected from Nand CR^(X), wherein each R^(X) is independently selected from H, halo,and C₁₋₄ alkyl;

D¹⁰ is O, S, NH or CH₂;

Ring F is a mono- or polycyclic ring selected from C₆₋₁₀ aryl, C₃₋₇cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl, each optionally substituted by 1, 2, 3, or 4substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),and S(O)₂NR^(c6)R^(d6), wherein the alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, NO₂, OR^(a6), SR^(a6)C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(NR^(e6))NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6),NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6),S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6);

each R^(a), R^(b), R^(c), R^(d), R^(a1), R^(b1), R^(c1), R^(d1), R^(a2),R^(b2), R^(c2), R^(d2), R^(a3), R^(b3), R^(c3), R^(d3), R^(a4), R^(b4),R^(c4), R^(d4), R^(a5), R^(b5), R^(c5), R^(d5), R^(a6), R^(b6), R^(c6),and R^(d6) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10membered heterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10membered heterocycloalkyl-C₁₋₄ alkyl of said R^(a), R^(b), R^(c), R^(d),R^(a1), R^(b1), R^(d), R^(d1)R^(a2), R^(b2), R^(c2), R^(d2), R^(a3),R^(b3), R^(c3), R^(d3), R^(a4), R^(b4), R^(c4), R^(d4), R^(as), R^(b5),R^(c5), R^(d5), R^(a6), R^(b6), R^(c6), and R^(d6) is optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c) and R^(d) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c1) and R^(d2) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c2) and R^(d2) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c3) and R^(d3) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c4) and R^(d4) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c5) and R^(d5) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c6) and R^(d6) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7) andS(O)₂NR^(c7)R^(d7);

R^(a7), R^(b7), R⁷, and R^(d7) are independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, and 4-10 membered heterocycloalkyl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl are each optionally substituted with 1, 2,or 3 substituents independently selected from OH, CN, amino, halo, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy;

each R^(e), R^(e1), R^(e2), R^(e3), R^(e4), Res, R^(e6) and R^(e7) isindependently selected from H, C₁₋₄ alkyl, and CN;

a is 0 or 1;

b is 0, 1, 2, or 3;

c is 0, 1, or 2;

d is 0, 1, or 2;

m is 0 or 1;

n is 0 or 1;

p is 0 or 1;

q is 0 or 1;

r is 0 or 1;

s1 is 0, 1, or 2;

s2 is 0, 1, 2, or 3;

t1 is 0 or 1;

t2 is 0 or 1;

t3 is 0 or 1;

u is 0, 1, 2, or 3;

v is 0 or 1; and

w is 0 or 1;

wherein any aforementioned heteroaryl or heterocycloalkyl groupcomprises 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom O, N, and S; and

wherein one or more ring-forming C or N atoms of any aforementionedheterocycloalkyl group is optionally substituted by an oxo (═O) group.

In some embodiments, A is the group having the formula A-1.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein:

X is Cl, Br, CH₃, CF₃, CN, OCH₃, ethyl, cyclopropyl, SCH₃, or isopropyl;

A is a group having the formula (A-1):

Y¹, Y², and Y³ are each independently selected from O, S, NR^(Y), C(═O),C(═O)O, C(═O)NR^(Y), S(═O), S(═O)₂, S(═O)NR^(Y), S(═O)₂NR^(Y) orNR^(Y)C(═O)NR^(Y), wherein each R^(Y) is independently H or C₁₋₄ alkyl;

L is C₁₋₃ alkylene, O, S, NR^(Y), C(═O), C(═O)O, C(═O)NR^(Y), S(═O),S(═O)NR^(Y), or NR^(Y)C(═O)NR^(Y);

Z is H, Cy^(Z), halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(e)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl of Z are each optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from Cy^(Z),halo, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d);

Cy^(Z) is selected from C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl, each optionallysubstituted by 1, 2, 3, or 4 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1), wherein thealkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionally substituted with 1,2, or 3 substituents independently selected from halo, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d);

Ring D is a monocyclic or polycyclic 4-10 membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 groups independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, or 3 groups independently selected from halo, CN, NO₂,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are eachindependently selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, CN, NO₂, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR³C(O)OR^(a3),NR³C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3) S(O)₂R^(b3),NR^(c3) S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10membered heterocycloalkyl-C₁₋₄ alkyl of said R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, and R¹² are each optionally substituted with 1, 2, 3,4, or 5 substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a3),SR^(a3)C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);

or R¹ and R³ together with the carbon atoms to which they are attachedform a C₅₋₁₀ cycloalkyl ring or a 5-10 membered heterocycloalkyl ring,each optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3) S(O)₂R^(b3),NR^(c3) S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3);

or R³ and R⁵ together with the carbon atoms to which they are attachedform a C₅₋₁₀ cycloalkyl ring or a 5-10 membered heterocycloalkyl ring,each optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3);

or R⁷ and R⁹ together with the carbon atoms to which they are attachedform a C₅₋₁₀ cycloalkyl ring or a 5-10 membered heterocycloalkyl ring,each optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3);

or R⁹ and R¹¹ together with the carbon atoms to which they are attachedform a C₅₋₁₀ cycloalkyl ring or a 5-10 membered heterocycloalkyl ring,each optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3) S(O)₂R^(b3),NR^(c3) S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3);

or R⁵ and R⁷ together with the carbon atoms to which they are attachedand together with Y² form a 5-10 membered heterocycloalkyl ringoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3) S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3);

or R¹ and R³ together form a double bond between the carbon atoms towhich they are attached;

or R³ and R⁵ together form a double bond between the carbon atoms towhich they are attached;

or R⁷ and R⁹ together form a double bond between the carbon atoms towhich they are attached;

or R⁹ and R¹¹ together form a double bond between the carbon atoms towhich they are attached;

or R⁹, R¹⁰, R¹¹, and R¹² together form a triple bond between the carbonatoms to which they are attached;

each R^(a), R^(b), R^(c), R^(d), R^(a1), R^(b1), R^(c1), R^(d1), R^(a2),R^(b2), R^(c2), R^(d2), R^(a3), R^(b3), R^(c3), and R^(d3) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10membered heterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10membered heterocycloalkyl-C₁₋₄ alkyl of said R^(a), R^(b), R^(c), R^(d),R^(a1), R^(b1), R^(c1), R^(d1), R^(a2), R^(b2), R^(c2), R^(d2), R^(a3),R^(b3), R^(c3), and R^(d3) is optionally substituted with 1, 2, or 3substituents independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, OR^(a7), SR^(a7), C(O)R^(b)7,C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7),NR^(c7)R^(d7), NR^(c7)C(O)R^(b7), NR^(c7)C(O)NR^(c7)R^(d7),NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c) and R^(d) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c1) and R^(d2) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c2) and R^(d2) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c3) and R^(d3) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

R^(a7), R^(b7), R⁷, and R^(d7) are independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, and 4-10 membered heterocycloalkyl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl are each optionally substituted with 1, 2,or 3 substituents independently selected from OH, CN, amino, halo, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy;

each R^(e), R^(e1), R^(e2), R^(e3), and R^(e7) is independently selectedfrom H, C₁₋₄ alkyl, and CN;

a is 0 or 1;

m is 0 or 1;

n is 0 or 1;

p is 0 or 1;

q is 0 or 1;

r is 0 or 1;

wherein any aforementioned heteroaryl or heterocycloalkyl groupcomprises 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom O, N, and S; and

wherein one or more ring-forming C or N atoms of any aforementionedheterocycloalkyl group is optionally substituted by an oxo (═O) group.

In some embodiments, A is group having the formula (A-1a):

In some embodiments, A is group having the formula (A-1b):

In some embodiments, A is group having the formula (A-1c):

wherein Z¹ and Z² are each independently selected from N and CH, andwherein R is CN, Cl, or CF₃.

In some embodiments, A is group having the formula (A-1d):

wherein Z¹ and Z² are each independently selected from N and CH, andwherein R is CN, Cl, or CF₃.

In some embodiments, L is NR^(Y) or O. In some embodiments, L is NH₂ orO. In some embodiments, L is NR^(Y). In some embodiments, L is O. Insome embodiments, L is NH₂.

In some embodiments, X is CF₃, CH₃, CN, Cl or Br.

In some embodiments, Y¹ is NR^(Y) or O. In some embodiments, Y¹ isNR^(Y). In some embodiments, Y¹ is O. In some embodiments, Y¹ is NR^(Y),O, or S. In some embodiments, Y¹ is S.

In some embodiments, Y² is NR^(Y) or O. In some embodiments, Y² is O. Insome embodiments, Y² is NR^(Y), O, or S. In some embodiments, Y² isNR^(Y). In some embodiments, Y² is S.

In some embodiments, Y³ is C(═O). In some embodiments, Y³ is C(═O) orS(═O)₂. In some embodiments, Y³ is S(═O)₂.

In some embodiments, R^(Y) is H or C₁₋₄ alkyl. In some embodiments,R^(Y) is methyl. In some embodiments, R^(Y) is H.

In some embodiments, Z is H, Cy^(Z), halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,CN, NO₂, OR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), NR^(c)R^(d),and NR^(c)C(O)R^(b); wherein said C₁₋₆ alkyl and C₁₋₆ haloalkyl of Z areeach optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from Cy^(Z), halo, CN, NO₂, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), and NR^(c)C(O)R^(b). In some embodiments, Z is Cy^(Z).

In some embodiments, Cy^(Z) is selected from 5-10 membered heteroaryland 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2,3, or 4 substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1), wherein thealkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionally substituted with 1,2, or 3 substituents independently selected from halo, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1).

In some embodiments, Cy^(Z) is 5-10 membered heteroaryl, optionallysubstituted by CN, CF₃, or Cl. In some embodiments, Cy^(Z) is pyridinylor pyrimidinyl, each optionally substituted by CN, CF₃, or Cl. In someembodiments, Cy^(Z) is 5-10 membered heteroaryl, optionally substitutedby CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, or NR^(c1)R^(d1), whereinC₁₋₆alkyl is optionally substituted with CN or NR^(c1)R^(d1). In someembodiments, Cy^(Z) is pyridinyl, pyrimidinyl, or pyrazinyl, eachoptionally substituted by CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, orNR^(c1)R^(d1) wherein C₁₋₆alkyl is optionally substituted with CN orNR^(c1)R^(d1). In some embodiments, Cy^(Z) is pyridinyl, pyrimidinyl,pyrazinyl, or thiazolyl, each optionally substituted by CN, C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, or NR^(c1)R^(d1), wherein C₁₋₆alkyl is optionallysubstituted with CN or NR^(c1)R^(d1).

In some embodiments, Ring D is a monocyclic or polycyclic 4-10 memberedheterocycloalkyl group optionally substituted with 1, 2, or 3 groupsindependently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(a), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), wherein the C₁₋₆ alkyl is optionally substituted with1, 2, or 3 groups independently selected from halo, CN, NO₂, OR^(a2),C(O)R^(b2), NR^(c2)R^(d2), and NR^(c2)C(O)R^(b2)In some embodiments,Ring D is a monocyclic 4-10 membered heterocycloalkyl group.

In some embodiments, Ring D is piperazinyl. In some embodiments, Ring Dis piperazinyl, dihydropyridazinyl, diazepanyl, pyrrolidinyl, orhexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl. In some embodiments, Ring D ispiperazinyl, dihydropyridazinyl, diazepanyl, pyrrolidinyl, orhexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl, each optionally substituted with1, 2, or 3 groups independently selected from halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), wherein the C₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 groups independently selected from halo, CN,NO₂, OR^(a2), C(O)R^(b2), NR^(c2)R^(d2), and NR^(c2)C(O)R^(b2). In someembodiments, Ring D is piperazinyl optionally substituted by C₁₋₆ alkyl.

In some embodiments, Ring D is piperazinyl optionally substituted by oneto eight deuterium atoms. In some embodiments, Ring D ispiperazin-1-yl-2,2,3,3,5,5,6,6-d8.

In some embodiments, R¹ is H, halo, OR^(a3), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a3) or NR^(c3)R^(d3). In someembodiments, R¹ is H, halo, OR^(a3), C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl, or 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl or 4-10 membered heterocycloalkyl-C₁₋₄ alkyl isoptionally substituted with OR^(a3) or NR^(c3)R^(d3).

In some embodiments, R¹ is C₁₋₆ alkyl. In some embodiments, R¹ is C₁₋₆alkyl, optionally substituted with OR^(a3). In some embodiments, R¹ isH. In some embodiments, R¹ is methyl, ethyl, or isopropyl. In someembodiments, R¹ is methoxymethyl or hydroxymethyl. In some embodiments,R¹ is phenyl, phenylmethyl, or pyridinyl. In some embodiments, R¹ is5-10 membered heteroaryl-C₁₋₄ alkyl or 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl. In some embodiments, R¹ is pyridinylmethyl,piperidinylmethyl, or morpholinylmethyl. In some embodiments, R¹ istetrahydrofuranyl or piperidinyl. In some embodiments, R¹ is phenyl,pyridinyl, tetrahydrofuranyl or piperidinyl.

In some embodiments, R² is H, halo, OR^(a3), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a3) or NR^(c3)R^(d3). In someembodiments, R² is H, halo, OR^(a3), C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl, or 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl or 4-10 membered heterocycloalkyl-C₁₋₄ alkyl isoptionally substituted with OR^(a3) or NR^(c3)R^(d3).

In some embodiments, R² is OR^(a3). In some embodiments, R² is H.

In some embodiments, R³ is H, halo, OR^(a3), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a3) or NR^(c3)R^(d3).

In some embodiments, R³ is H. In some embodiments, R³ is methyl, ethyl,or isopropyl.

In some embodiments, R³ is methoxymethyl or hydroxymethyl. In someembodiments, R³ is phenyl, phenylmethyl, or pyridinyl.

In some embodiments, R⁴ is H, halo, OR^(a3), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a3) or NR^(c3)R^(d3).

In some embodiments, R⁴ is H.

In some embodiments, R⁵ is H, halo, OR^(a3), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a3) or NR^(c3)R^(d3).

In some embodiments, R⁵ is H. In some embodiments, R⁵ is methyl, ethyl,or isopropyl.

In some embodiments, R⁵ is methoxymethyl or hydroxymethyl. In someembodiments, R⁵ is phenyl, phenylmethyl, or pyridinyl.

In some embodiments, R⁶ is H, halo, OR^(a3), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a3) or NR^(c3)R^(d3).

In some embodiments, R⁶ is H.

In some embodiments, R⁷ is H, halo, OR^(a3), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a3) or NR^(c3)R^(d3).

In some embodiments, R⁷ is C₁₋₆ alkyl. In some embodiments, R⁷ ismethyl.

In some embodiments, R⁸ is H, halo, OR^(a3), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a3) or NR^(c3)R^(d3).

In some embodiments, R⁸ is H.

In some embodiments, R⁹ is H, halo, OR^(a3), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a3) or NR^(c3)R^(d3).

In some embodiments, R⁹ is H.

In some embodiments, R¹⁰ is H, halo, OR^(a3), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a3) or NR^(c3)R^(d3).

In some embodiments, R¹⁰ is H.

In some embodiments, R¹¹ is H, halo, OR^(a3), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a3) or NR^(c3)R^(d3).

In some embodiments, R¹¹ is H.

In some embodiments, R¹² is H, halo, OR^(a3), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a3) or NR^(c3)R^(d3).

In some embodiments, R¹² is H.

In some embodiments, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are each H.

In some embodiments, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are each H.

In some embodiments, R¹, R², R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each H.

In some embodiments, R², R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each H.

In some embodiments, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each H In someembodiments, R³ and R⁵ together with the carbon atoms to which they areattached form a C₅₋₁₀ cycloalkyl ring or a 5-10 memberedheterocycloalkyl ring, each optionally substituted with 1, 2, or 3substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3) S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3).

In some embodiments, R³ and R⁵ together with the carbon atoms to whichthey are attached form a C₅₋₁₀ cycloalkyl ring or a 5-10 memberedheterocycloalkyl ring.

In some embodiments, R³ and R⁵ together with the carbon atoms to whichthey are attached form a tetrahydrofuranyl ring.

In some embodiments, R³ and R⁵ together with the carbon atoms to whichthey are attached form a cyclobutyl or cyclopentyl ring.

In some embodiments, R⁵ and R⁷ together with the carbon atoms to whichthey are attached and together with Y² form a 5-10 memberedheterocycloalkyl ring optionally substituted with 1, 2, or 3substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3) S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3).

In some embodiments, R⁵ and R⁷ together with the carbon atoms to whichthey are attached and together with Y² form a 5-10 memberedheterocycloalkyl ring.

In some embodiments, R⁵ and R⁷ together with the carbon atoms to whichthey are attached and together with Y² form a tetrahydrofuranyl ring ortetrahydropyranyl ring. In some embodiments, R⁵ and R⁷ together with thecarbon atoms to which they are attached and together with Y² form atetrahydrofuranyl ring, tetrahydropyranyl ring, or pyrrolidinyl ring. Insome embodiments, R⁵ and R⁷ together with the carbon atoms to which theyare attached and together with Y² form a pyrrolidinyl ring.

In some embodiments, R^(a3) is C₁₋₆ alkyl or H. In some embodiments,R^(a3) is methyl. In some embodiments, R^(a3) is H.

In some embodiments, R^(c3) and R^(d3) are each independently selectedfrom C₁₋₆ alkyl and H.

In some embodiments, R^(c3) is C₁₋₆ alkyl or H. In some embodiments,R^(d3) is C₁₋₆ alkyl or H. In some embodiments, R^(c3) and R^(d3) areeach methyl. In some embodiments, R^(c3) and R^(d3) are each H.

In some embodiments, m is 1.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, p is 0.In some embodiments, p is 1.

In some embodiments, q is 0. In some embodiments, q is 1.

In some embodiments, r is 0.

In some embodiments, a is 0.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, having Formula IIa:

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, having Formula IIb:

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, having Formula IIc:

wherein Z¹ and Z² are each independently selected from N and CH, andwherein R is CN, Cl, or CF₃.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, having Formula IId:

wherein Z¹ and Z² are each independently selected from N and CH, andwherein R is CN, Cl, or CF₃.

In some embodiments, A is the group having the formula A-2.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein:

X is Cl, Br, CH₃, CF₃, CN, OCH₃, cyclopropyl, SCH₃, or isopropyl;

A is a group having the formula (A-2):

L is C₁₋₃ alkylene, O, S, NR^(Y), C(═O), C(═O)O, C(═O)NR^(Y), S(═O),S(═O)NR^(Y), or NR^(Y)C(═O)NR^(Y);

Z is H, Cy^(Z), halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl of Z are each optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from Cy^(Z),halo, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d);

Cy^(Z) is selected from C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl, each optionallysubstituted by 1, 2, 3, or 4 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1), wherein thealkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionally substituted with 1,2, or 3 substituents independently selected from halo, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1) NR^(c1)S(O)R^(b1),NR^(c11)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

R¹³, R¹⁴, and R¹⁵ are each independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₇cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, CN,NO₂, OR^(a4), SR^(a4)C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)S(O)R^(b4), NR⁴S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl of said R¹³, R¹⁴, and R¹⁵ are eachoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4),C(═NR^(e4))R^(b4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),and S(O)₂NR^(c4)R^(d4);

Q¹, Q², and Q³ are each a group of formula (B-1):

Y⁴, Y⁵, and Y⁶ are each independently selected from O, S, NR^(Y), C(═O),C(═O)O, C(═O)NR^(Y), S(═O), S(═O)₂, S(═O)NR^(Y), S(═O)₂NR^(v) orNR^(Y)C(═O)NR^(Y);

G¹ is —C(R^(G))(R^(H))— or a group of formula (C-1), (C-2), or (C-3):

G² is —C(R^(I))(R^(J))— or a group of formula (C-1), (C-2), or (C-3);

R^(A), R^(B), R, R^(D), R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), R^(K),R^(L), R^(M), and R^(N) are each independently selected from H, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₇cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, CN,NO₂, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), C(═NR^(e))NR^(c5)R^(d5),NR^(c5)C(═NR^(e))NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₇cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, and 4-10 membered heterocycloalkyl-C₁₋₄ alkyl ofsaid R^(A), R^(B), R^(C), R^(D), R^(E), R^(F), R^(G), R^(H), R^(I),R^(J), R^(K), R^(L), R^(M), and R^(N) are each optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);

or R^(G) and R^(I) together with the carbon atoms to which they areattached and together with Y⁵ form a 5-10 membered heterocycloalkyl ringoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR³C(O)NR^(c3)R^(d3),C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3)NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3);

or R^(C) and R^(E) together form a double bond between the carbon atomsto which they are attached;

or R^(E) and R^(G) together form a double bond between the carbon atomsto which they are attached;

or R^(I) and R^(K) together form a double bond between the carbon atomsto which they are attached;

or R^(K) and R^(M) together form a double bond between the carbon atomsto which they are attached;

or R^(K), R^(L), R^(M), and R^(N) together form a triple bond betweenthe carbon atoms to which they are attached;

D¹ and D² are each independently selected from N and CH;

D³, D⁴, D⁵, D⁶, D⁷, D⁸, and D⁹ are each independently selected from Nand CR^(X), wherein each R^(X) is independently selected from H, halo,and C₁₋₄ alkyl;

D¹⁰ is O, S, NH or CH₂;

Ring F is a mono- or polycyclic ring selected from C₆₋₁₀ aryl, C₃₋₇cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl, each optionally substituted by 1, 2, 3, or 4substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),and S(O)₂NR^(c6)R^(d6), wherein the alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, NO₂, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),and S(O)₂NR^(c6)R^(d6);

each R^(a), R^(b), R^(c), R^(d), R^(a1), R^(b1), R^(c1), R^(d1), R^(a3),R^(b3), R^(c3), R^(d3), R^(a4), R^(b4), R^(c4), R^(d4), R^(as), R^(b5),R^(c5), R^(d5), R^(a6), R^(b6), R^(c6), and R^(d6) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl of said R^(a), R^(b), R^(c), R^(d), R^(a1),R^(b1), R^(c1), R^(d1), R^(a2), R^(b2), R^(c2), R^(d2), R^(a3), R^(b3),R^(c3), R^(d3), R^(a4), R^(b4), R^(c4), R^(d4), R^(a5), R^(b5), R^(c5),R^(d5), R^(a6), R^(b6), R^(c6), and R^(d6) is optionally substitutedwith 1, 2, or 3 substituents independently selected from halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, OR^(a7), SR^(a7),C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c) and R^(d) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c3) and R^(d3) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c4) and R^(d4) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c5) and R^(d5) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c6) and R^(d6) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

R^(a7), R^(b7), R^(c7), and R^(d7) are independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, and 4-10 membered heterocycloalkyl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl are each optionally substituted with 1, 2,or 3 substituents independently selected from OH, CN, amino, halo, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy;

each R^(e), R^(e1), R^(e3), R^(e4), R^(e5), R^(e6) and R^(e7) isindependently selected from H, C₁₋₄ alkyl, and CN;

a is 0 or 1;

b is 0, 1, 2, or 3;

c is 0, 1, or 2;

d is 0, 1, or 2;

m is 0 or 1;

n is 0 or 1;

p is 0 or 1;

q is 0 or 1;

r is 0 or 1;

s1 is 0, 1, or 2;

s2 is 0, 1, 2, or 3;

v is 0 or 1; and

w is 0 or 1;

wherein any aforementioned heteroaryl or heterocycloalkyl groupcomprises 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom O, N, and S; and

wherein one or more ring-forming C or N atoms of any aforementionedheterocycloalkyl group is optionally substituted by an oxo (═O) group.

In some embodiments, Q¹ is a group of formula (B-1a):

In some embodiments, Q¹ is a group of formula (B-1b):

In some embodiments, Q¹ is a group of formula (B-1c):

wherein Z¹ and Z² are each independently selected from N and CH, andwherein R is CN, Cl, or CF₃.

In some embodiments, X is CF₃, CH₃, CN, Cl, or Br.

In some embodiments, Ring F is 4-10 membered heterocycloalkyl or C₃₋₇cycloalkyl optionally substituted with C₁₋₆ alkyl, wherein said C₁₋₆alkyl is optionally substituted with OR^(a6)In some embodiments, Ring Fis 4-10 membered heterocycloalkyl or C₃₋₇ cycloalkyl, each optionallysubstituted with methyl.

In some embodiments, Ring F is piperazinyl, piperidinyl, pyrrolidinyl,5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl,2,8-diazaspiro[4.5]decanyl, 2,5-diazabicyclo[2.2.2]octanyl,1,4-diazepanyl, azetidinyl, 2,6-diazaspiro[3.3]heptanyl,2,6-diazaspiro[3.4]octanyl, octahydropyrrolo[3,2-b]pyrrolyl,2,7-diazaspiro[4.4]nonanyl, 2,5-diazabicyclo[2.2.1]heptanyl,octahydropyrrolo[3,4-c]pyrrolyl, or 2,7-diazaspiro[3.5]nonanyl.

In some embodiments, Ring F is piperazinyl.

In some embodiments, Ring F is cyclohexyl.

In some embodiments, Ring F is 4-10 membered heterocycloalkyl,optionally substituted by an oxo (═O) group.

In some embodiments, Z is Cy^(Z), C₁₋₆ alkyl, or C(O)R^(b), wherein saidC₁₋₆ alkyl is optionally substituted by halo. In some embodiments, Z isCF₃.

In some embodiments, Cy^(Z) is selected from 5-10 membered heteroaryland C₆₋₁₀ aryl, optionally substituted by C₁₋₆ alkyl, CN or CF₃, whereinsaid C₁₋₆ alkyl is optionally substituted with CN.

In some embodiments, Cy^(Z) is pyridinyl, pyrimidinyl, or pyrazinyl,optionally substituted by C₁₋₆ alkyl, CN, Cl, S(O)₂R^(b1), or CF₃.

In some embodiments, Cy^(Z) is pyridinyl, pyrimidinyl, or pyrazinyl,optionally substituted by methyl, CN, Cl, CF₃, or S(O)₂CH₃.

In some embodiments, Cy^(Z) is phenyl, optionally substituted withcyanomethyl or CN.

In some embodiments, R^(b) is C₁₋₆ alkyl. In some embodiments, R^(b) ismethyl.

In some embodiments, Y⁴ is O or NR^(Y). In some embodiments, Y⁴ is O. Insome embodiments, Y⁴ is NR^(Y).

In some embodiments, Y⁵ is O, NR^(Y), or C(═O)NR^(Y).

In some embodiments, Y⁶ is C(═O) or C(═O)NR^(Y).

In some embodiments, R^(Y) is H or C₁₋₄ alkyl. In some embodiments,R^(Y) is H. In some embodiments, R^(Y) is methyl.

In some embodiments, L is O or NR^(Y).

In some embodiments, G¹ is —C(R^(G))(R^(H))—.

In some embodiments, G² is C-1. In some embodiments, D¹ and D² are eachCH and D¹⁰ is CH₂.In some embodiments, D¹ is CH, D² is N, and D¹⁰ isCH₂.In some embodiments, D³ is CH, D⁴ is N, D⁵ is CH. In someembodiments, D¹⁰ is CH₂.

In some embodiments, b is 0, c is 1, and d is 1. In some embodiments, bis 0, c is 2, and d is 0. In some embodiments, b is 0, c is 0, and d is0. In some embodiments, b is 0, c is 1, and d is 0.

In some embodiments, G² is C-2. In some embodiments, D³, D⁴, and D⁵ areeach CR^(X), wherein each R^(X) is independently selected from H, halo,and C₁₋₄ alkyl.

In some embodiments, G² is C-3. In some embodiments, D⁶, D⁷, and D⁹ areCR^(X), and D⁸ is N. In some embodiments, D⁶ and D⁷ are each N, and D⁸and D⁹ are each CR^(X). In some embodiments, D⁶, D⁷, D⁸, and D⁹ are eachCR^(X). In some embodiments, D⁶, D⁸, and D⁹ are each CR^(X), and D⁷ isN. In some embodiments, D⁶, D⁷, and D⁸ are each CR^(X) and D⁹ is N. Insome embodiments, D⁶ and D⁸ are each N, and D⁷ and D⁹ are each CR^(X).

In some embodiments, each R^(X) is H or halo. In some embodiments, R^(X)is H or F. In some embodiments, R^(X) is H.

In some embodiments, G² is —C(R^(I))(R^(J))—

In some embodiments, R¹³ is C₁₋₆ alkyl, OR^(a4), CN, or NR^(c4)R^(d4),wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or 3substituents independently selected from halo and OR^(a4) andNR^(c4)R^(d4).

In some embodiments, R¹³ is methyl. In some embodiments, R¹³ is CN. Insome embodiments, R¹³ is CF₃. In some embodiments, R¹³ is amino. In someembodiments, R¹³ is aminomethyl.

In some embodiments, R^(A) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(A) is C₁₋₆ alkyl or H. In some embodiments,R^(A) is methyl. In some embodiments, R^(A) is H.

In some embodiments, R^(B) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(B) is C₁₋₆ alkyl or H. In some embodiments,R^(B) is methyl. In some embodiments, R^(B) is H.

In some embodiments, R^(c) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(c) is C₁₋₆ alkyl or H. In some embodiments,R^(c) is methyl. In some embodiments, R^(c) is H.

In some embodiments, R^(D) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(D) is C₁₋₆ alkyl or H. In some embodiments,R^(D) is methyl. In some embodiments, R^(D) is H.

In some embodiments, R^(E) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(E) is C₁₋₆ alkyl or H. In some embodiments,R^(E) is methyl. In some embodiments, R^(E) is H.

In some embodiments, R^(F) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(F) is C₁₋₆ alkyl or H. In some embodiments, R ismethyl. In some embodiments, R^(E) is H.

In some embodiments, R^(G) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(G) is C₁₋₆ alkyl or H. In some embodiments,R^(G) is methyl. In some embodiments, R^(G) is H.

In some embodiments, R^(H) is H, halo, OR⁵, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(H) is C₁₋₆ alkyl or H. In some embodiments,R^(H) is methyl. In some embodiments, R^(H) is H.

In some embodiments, R^(I) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(I) is C₁₋₆ alkyl or H. In some embodiments,R^(I) is methyl. In some embodiments, R^(I) is H.

In some embodiments, R^(J) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(J) is C₁₋₆ alkyl or H. In some embodiments,R^(I) is methyl. In some embodiments, R^(J) is H.

In some embodiments, R^(K) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(K) is C₁₋₆ alkyl or H. In some embodiments,R^(K) is methyl. In some embodiments, R^(K) is H.

In some embodiments, R^(L) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(L) is C₁₋₆ alkyl or H. In some embodiments,R^(L) is methyl. In some embodiments, R^(L) is H.

In some embodiments, R^(M) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(M) is C₁₋₆ alkyl or H. In some embodiments,R^(M) is methyl. In some embodiments, R^(M) is H.

In some embodiments, R^(N) is H, halo, OR⁵, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(N) is C₁₋₆ alkyl or H. In some embodiments,R^(N) is methyl. In some embodiments, R^(N) is H.

In some embodiments, R^(I) and R^(K) together form a double bond betweenthe carbon atoms to which they are attached.

In some embodiments, R^(K) and R^(M) together form a double bond betweenthe carbon atoms to which they are attached.

In some embodiments, R^(K), R^(L), R^(M), and R^(N) together form atriple bond between the carbon atoms to which they are attached.

In some embodiments, R^(G) and R^(I) together with the carbon atoms towhich they are attached and together with Y⁵ form a 5-10 memberedheterocycloalkyl ring optionally substituted with 1, 2, or 3substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3)C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3).

In some embodiments, R^(G) and R^(I) together with the carbon atoms towhich they are attached and together with Y⁵ form a tetrahydrofuranylring.

In some embodiments, R^(a6) is H.

In some embodiments, R^(b1) is C₁₋₆ alkyl. In some embodiments, R^(b1)is methyl.

In some embodiments, R^(a4) is H or C₁₋₆ alkyl. In some embodiments,R^(a4) is methyl.

In some embodiments, R^(c4) and R^(d4) are each H.

In some embodiments, R^(c5) and R^(d5) are each H.

In some embodiments, R^(v) is H.

In some embodiments, a is 0. In some embodiments, a is 1.

In some embodiments, s1 is 0. In some embodiments, s1 is 1. In someembodiments, s1 is 2.

In some embodiments, s2 is 0. In some embodiments, s2 is 1. In someembodiments, s2 is 2.

In some embodiments, v is 0. In some embodiments, v is 1.

In some embodiments, w is 0. In some embodiments, w is 1.

In some embodiments, m is 0. In some embodiments, m is 1.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, in q is 0. In some embodiments, q is 1.

In some embodiments, r is 0. In some embodiments, r is 1.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, having Formula IIIa:

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, having Formula IIIb:

In some embodiments, A is the group having the formula A-3.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein:

X is Cl, Br, CH₃, CF₃, CN, OCH₃, ethyl, cyclopropyl, SCH₃, or isopropyl;

A is a group having the formula (A-3):

Y¹, Y², and Y³ are each independently selected from O, S, NR^(Y), C(═O),C(═O)O, C(═O)NR^(Y), S(═O), S(═O)₂, S(═O)NR^(Y), S(═O)₂NR^(Y) orNR^(Y)C(═O)NR^(Y), wherein each R^(Y) is independently H or C₁₋₄ alkyl;

L is C₁₋₃ alkylene, O, S, NR^(Y), C(═O), C(═O)O, C(═O)NR^(Y), S(═O),S(═O)NR^(Y), or NR^(Y)C(═O)NR^(Y);

Z is H, Cy^(Z), halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(C)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl of Z are each optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from Cy^(Z),halo, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d);

Cy^(Z) is selected from C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl, each optionallysubstituted by 1, 2, 3, or 4 substituents independently selected fromhalo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1), wherein thealkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionally substituted with 1,2, or 3 substituents independently selected from halo, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c) S(O)R^(b1), NR^(c)1S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

R¹³, R¹⁴, and R¹⁵ are each independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₇cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, CN,NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl of said R¹³, R¹⁴, and R¹⁵ are eachoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4),C(═NR^(e4))R^(b4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),and S(O)₂NR^(c4)R^(d4);

Ring E is a mono- or polycyclic ring selected from C₆₋₁₀ aryl, C₃₋₇cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl;

Q² and Q³ are each a group of formula (B-1):

Y⁴, Y⁵, and Y⁶ are each independently selected from O, S, NR^(Y), C(═O),C(═O)O, C(═O)NR^(Y), S(═O), S(═O)₂, S(═O)NR^(Y), S(═O)₂NR^(Y) orNR^(Y)C(═O)NR^(Y);

G¹ is —C(R^(G))(R^(H))— or a group of formula (C-1), (C-2), or (C-3):

G² is —C(R^(I))(R^(J))— or a group of formula (C-1), (C-2), or (C-3);

R^(A), R^(B), R, R^(D), R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), R^(K),R^(L), R^(M), and R^(N) are each independently selected from H, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₇cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, CN,NO₂, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), C(═NR^(e))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, C₃₋₇cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, and 4-10 membered heterocycloalkyl-C₁₋₄ alkyl ofsaid R^(A), R^(B), R^(C), R^(D), R^(E), R^(F), R^(G), R^(H), R^(I),R^(J), R^(K), R^(L), R^(M), and R^(N) are each optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂,OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);

or R^(G) and R^(I) together with the carbon atoms to which they areattached and together with Y⁵ form a 5-10 membered heterocycloalkyl ringoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, CN, NO₂, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3) S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3);

or R^(C) and R^(E) together form a double bond between the carbon atomsto which they are attached;

or R^(E) and R^(G) together form a double bond between the carbon atomsto which they are attached;

or R^(I) and R^(K) together form a double bond between the carbon atomsto which they are attached;

or R^(K) and R^(M) together form a double bond between the carbon atomsto which they are attached;

or R^(K), R^(L), R^(M), and R^(N) together form a triple bond betweenthe carbon atoms to which they are attached;

D¹ and D² are each independently selected from N and CH;

D³, D⁴, D⁵, D⁶, D⁷, D⁸, and D⁹ are each independently selected from Nand CR^(X), wherein each R^(X) is independently selected from H, halo,and C₁₋₄ alkyl;

D¹⁰ is O, S, NH or CH₂;

Ring F is a mono- or polycyclic ring selected from C₆₋₁₀ aryl, C₃₋₇cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl, each optionally substituted by 1, 2, 3, or 4substituents independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, NO₂, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),and S(O)₂NR^(c6)R^(d6), wherein the alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, CN, NO₂, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(NR^(e6))NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6),NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6),S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6);

each R^(a), R^(b), R^(c), R^(d), R^(a1), R^(b1), R^(c1), R^(d1), R^(a3),R^(b3), R^(c3), R^(d3), R^(a4), R^(b4), R^(c4), R^(d4), R^(a5), R^(b5),R^(c5), R^(d5), R^(a6), R^(b6), R^(c6), and R^(d6) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl of said R^(a), R^(b), R^(c), R^(d), R^(a1),R^(b1), R^(c1), R^(d1), R^(a2), R^(b2), R^(c2), R^(d2), R^(a3), R^(b3),R^(c3), R^(d3), R^(a4), R^(b4), R^(c4), R^(d4), R^(a5), R^(b5), R^(c5),R^(d5), R^(a6), R^(b6), R^(c6), and R^(d6) is optionally substitutedwith 1, 2, or 3 substituents independently selected from halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN, OR^(a7), SR^(a7),C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7), OC(O)R^(b7),OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c) and R^(d) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c1) and R^(d1) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c3) and R^(d3) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c4) and R^(d4) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c5) and R^(d5) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

or R^(c6) and R^(d6) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl group optionally substituted with1, 2, or 3 substituents independently selected from CN, halo, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CN,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)C(O)OR^(a7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c3)R^(d7), S(O)R^(b7), S(O)NR^(c7)R^(d7),S(O)₂R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), andS(O)₂NR^(c7)R^(d7);

R^(a7), R^(b7), R⁷, and R^(d7) are independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₇cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, and 4-10 membered heterocycloalkyl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl are each optionally substituted with 1, 2,or 3 substituents independently selected from OH, CN, amino, halo, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy;

each R^(e), R^(e1), R^(e3), R^(e4), R^(e5), R^(e6) and R^(e7) isindependently selected from H, C₁₋₄ alkyl, and CN;

a is 0 or 1;

b is 0, 1, 2, or 3;

c is 0, 1, or 2;

d is 0, 1, or 2;

m is 0 or 1;

n is 0 or 1;

p is 0 or 1;

q is 0 or 1;

r is 0 or 1;

t1 is 0 or 1;

t2 is 0 or 1;

t3 is 0 or 1;

u is 0, 1, 2, or 3;

v is 0 or 1; and

w is 0 or 1;

wherein any aforementioned heteroaryl or heterocycloalkyl groupcomprises 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom O, N, and S; and

wherein one or more ring-forming C or N atoms of any aforementionedheterocycloalkyl group is optionally substituted by an oxo (═O) group.

In some embodiments, Q² is a compound having the formula B-2a:

In some embodiments, Q² is a compound having the formula B-2a:

wherein Z¹ and Z² are each independently selected from N and CH, andwherein R is CN, Cl, or CF₃.

In some embodiments, Q³ is a compound having the formula B-3a:

In some embodiments, Q³ is a compound having the formula B-3b:

wherein Z¹ and Z² are each independently selected from N and CH, andwherein R is CN, Cl, or CF₃.

In some embodiments, X is Cl, Br, CH₃, CF₃, CN, OCH₃, ethyl,cyclopropyl, SCH₃, or isopropyl.

In some embodiments, Ring E is a mono- or polycyclic ring selected fromC₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl. In some embodiments, Ring E is a mono- or polycyclicring selected from C₆₋₁₀ aryl. In some embodiments, Ring E is a mono- orpolycyclic ring selected from 5-10 membered heteroaryl. In someembodiments, Ring E is a mono- or polycyclic ring selected from C₃₋₇cycloalkyl. In some embodiments, Ring E is a mono- or polycyclic ringselected from 4-10 membered heterocycloalkyl.

In some embodiments, Ring E is phenyl. In some embodiments, Ring E ispyridinyl. In some embodiments, Ring E is cyclohexyl. In someembodiments, Ring E is pyridine-4(1H)-onyl, 4-pyridonyl, or piperidinyl

In some embodiments, each R¹⁴ is independently selected from H, halo,OR^(a4), and C₁₋₆ alkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with CN, OR^(a7), NR^(c4)R^(d4), or NR^(c4)C(O)R^(b4).

In some embodiments, each R¹⁴ is independently selected from halo,methyl, ethyl, and cyanomethyl, each optionally substituted with CN,OR^(a), NR^(c4)R^(d4), or NR^(c4)C(O)R^(b4)

In some embodiments, each R¹⁵ is independently selected from H, halo,CN, NR^(c4)R^(d4), OR^(a4), C(O)R^(b4), NRc4C(O)R^(b4),C(O)NR^(c4)R^(d4) and C₁₋₆ alkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with CN, OR^(a7), NR^(c4)R^(d4), or NR^(c4)C(O)R^(b4).

In some embodiments, R¹⁵ is F or Cl. In some embodiments, each R¹⁵ isindependently selected from halo and OR^(a4). In some embodiments, eachR¹⁵ is independently selected from halo and NR^(c4)R^(d4). In someembodiments, each R¹⁵ is independently selected from halo,NR^(c4)C(O)R^(b4), C(O)R^(b4), and C(O)NR^(c4)R^(d4). In someembodiments, R¹⁵ is CN. In some embodiments, R¹⁵ is halo. In someembodiments, R¹⁵ is 4-10 membered heterocycloalkyl, optionallysubstituted with C₁₋₆ alkyl, NR^(c4)R^(d4) or C(O)R^(b4). In someembodiments, R¹⁵ is morpholinyl, piperidinyl, pyrrolidinyl, optionallysubstituted with OR^(a4), NR^(c4)R^(d4) or C(O)R^(b4).

In some embodiments, R^(a4) is selected from C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl, cycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄alkyl, and 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, each optionallysubstituted with C₁₋₄ alkyl, OR^(a7), NR^(c7)R^(d7), C(O)NR^(c7)R^(d7),C(O)R^(b7), C(O)OR^(a7) or NR^(c7)C(O)R^(b7).

In some embodiments, R^(a4) is H or C₁₋₆ alkyl. In some embodiments,R^(a4) is pyridinyl. In some embodiments, R^(a4) is phenyl. In someembodiments, R^(a4) is pyridinylmethyl, pyridinylethyl,tetrahydropyranylmethyl, tetrahydrofuranylmethyl, piperidinylmethyl,piperidinylethyl, morpholinylethyl, piperazinylethyl,pyrrolidinylmethyl. In some embodiments, R^(a4) is methyl, ethyl, orisopropyl. In some embodiments, R^(a4) is piperidinyl,tetrahydropyranyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, eachoptionally substituted by an oxo (═O) group, C₁₋₄ alkyl, OR^(a7),NR^(c7)R^(d7), C(O)NR^(c7)R^(d7), C(O)R^(b7), or NR^(c7)C(O)R^(b7). Insome embodiments, R^(a4) is pyrimidinyl.

In some embodiments, R^(b4) is C₁₋₆ alkyl. In some embodiments, R^(b4)is methyl.

In some embodiments, R⁴ is H or C₁₋₆ alkyl. In some embodiments, R⁴ ismethyl.

In some embodiments, R^(d4) is H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl,optionally substituted with 1, 2, 3, or 4 substituents independentlyselected from C₁₋₆ alkyl, C(O)R^(b7), and C(O)OR^(a7). In someembodiments, R^(d4) is methyl. In some embodiments, R^(d4) istetrehydrofuranylmethyl, pyridinylmethyl, pyridinylethyl, morpholinyl,piperidinyl, tetrahydropyranyl, or pyridinyl.

In some embodiments, R^(a7) is H or C₁₋₆ alkyl. In some embodiments,R^(a7) is methyl.

In some embodiments, R^(b7) is H or C₁₋₆ alkyl.

In some embodiments, R^(c7) is H or C₁₋₆ alkyl.

In some embodiments, R^(d7) is H or C₁₋₆ alkyl.

In some embodiments, R^(b7) is H or methyl.

In some embodiments, R^(c7) is H or methyl.

In some embodiments, R^(d7) is H or methyl.

In some embodiments, Y⁴ is O.

In some embodiments, Y⁵ is O, NR^(Y), C(═O), or C(═O)NR^(Y).

In some embodiments, G¹ is —C(R^(G))(R^(H))—. In some embodiments, G¹ isC-2.

In some embodiments, D³, D⁴, and D⁵ are each CR^(X), wherein each R^(X)is independently selected from H, halo, and C₁₋₄ alkyl.

In some embodiments, R^(X) is H.

In some embodiments, G² is —C(R^(I))(R^(J))—. In some embodiments, G² isC-3.

In some embodiments, D⁶, D⁷, and D⁹ are each CR^(X), and D⁸ is N. Insome embodiments, D⁶ and D⁷ are each N, and D⁸ and D⁹ are each CR^(X).In some embodiments, D⁶, D⁷, D⁸, and D⁹ are each CR^(X). In someembodiments, D⁶, D⁸, and D⁹ are each CR^(X), and D⁷ is N. In someembodiments, D⁶, D⁷, and D⁸ are each CR^(X) and D⁹ is N. In someembodiments, D⁶ and D⁸ are each N, and D⁷ and D⁹ are each CR^(X). Insome embodiments, D⁶ and D⁹ are each N, and D⁷ and D⁸ are each CR^(X).

In some embodiments, G² is C-1.

In some embodiments, D¹ and D² are each N and D¹⁰ is CH₂.

In some embodiments, b is 0, c is 1, and d is 1.

In some embodiments, Ring F is 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, or C₃₋₇ cycloalkyl, each optionally substitutedwith C₁₋₆ alkyl, wherein said C₁₋₆ alkyl is optionally substituted withOR^(a6). In some embodiments, Ring F is 4-10 membered heterocycloalkylor C₃₋₇ cycloalkyl, each optionally substituted with methyl.

In some embodiments, Ring F is piperazinyl, piperidinyl, pyrrolidinyl,pyridinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl,2,8-diazaspiro[4.5]decanyl, 2,5-diazabicyclo[2.2.2]octanyl,1,4-diazepanyl, azetidinyl, 2,6-diazaspiro[3.3]heptanyl,2,6-diazaspiro[3.4]octanyl, octahydropyrrolo[3,2-b]pyrrolyl,2,7-diazaspiro[4.4]nonanyl, 2,5-diazabicyclo[2.2.1]heptanyl,octahydropyrrolo[3,4-c]pyrrolyl, 2,7-diazaspiro[3.5]nonanyl, or4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine.

In some embodiments, Ring F is piperzinyl. In some embodiments, Ring Fis cyclohexyl.

In some embodiments, Ring F is 4-10 membered heterocycloalkyl,optionally substituted by an oxo (═O) group.

In some embodiments, Z is Cy^(Z), CN, C₁₋₆ alkyl, or C(O)R^(b), whereinsaid C₁₋₆ alkyl is optionally substituted by halo. In some embodiments,Z is CF₃, CH₃, or CN. In some embodiments, Z is H.

In some embodiments, R^(b) is C₁₋₆ alkyl, optionally substituted withCN. In some embodiments, R^(b) is methyl.

In some embodiments, Cy^(Z) is selected from 5-10 membered heteroaryland C₆₋₁₀ aryl, each optionally substituted by C₁₋₆ alkyl, halo, CN orCF₃, wherein said C₁₋₆ alkyl is optionally substituted with CN. In someembodiments, Cy^(Z) is pyridinyl, pyrimidinyl, or pyrazinyl, eachoptionally substituted by C₁₋₆ alkyl, CN, Cl, F, S(O)₂R^(b1), or CF₃. Insome embodiments, Cy^(Z) is pyridinyl, pyrimidinyl, pyrazinyl, eachoptionally substituted by methyl, CN, Cl, F, CF₃, or S(O)₂CH₃. In someembodiments, Cy^(Z) is phenyl, optionally substituted with cyanomethylor CN.

In some embodiments, R^(b1) is C₁₋₆ alkyl. In some embodiments, R^(b1)is methyl.

In some embodiments, R^(A) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(A) is C₁₋₆ alkyl or H. In some embodiments,R^(A) is methyl. In some embodiments, R^(A) is H.

In some embodiments, R^(B) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(B) is C₁₋₆ alkyl or H. In some embodiments,R^(B) is methyl. In some embodiments, R^(B) is H.

In some embodiments, R^(c) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(c) is C₁₋₆ alkyl or H. In some embodiments,R^(c) is methyl. In some embodiments, R^(c) is H.

In some embodiments, R^(D) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(D) is C₁₋₆ alkyl or H. In some embodiments,R^(D) is methyl. In some embodiments, R^(D) is H.

In some embodiments, R^(E) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(E) is C₁₋₆ alkyl or H. In some embodiments,R^(E) is methyl. In some embodiments, R^(E) is H.

In some embodiments, R^(F) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(F) is C₁₋₆ alkyl or H. In some embodiments,R^(F) is methyl. In some embodiments, R^(E) is H.

In some embodiments, R^(G) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(G) is C₁₋₆ alkyl or H. In some embodiments,R^(G) is methyl. In some embodiments, R^(G) is H.

In some embodiments, R^(H) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(H) is C₁₋₆ alkyl or H. In some embodiments,R^(H) is methyl. In some embodiments, R^(H) is H.

In some embodiments, R^(I) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(I) is C₁₋₆ alkyl or H. In some embodiments,R^(I) is methyl. In some embodiments, R^(I) is H.

In some embodiments, R^(J) is H, halo, OR⁵, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(J) is C₁₋₆ alkyl or H. In some embodiments,R^(J) is methyl. In some embodiments, R^(J) is H.

In some embodiments, R^(K) is H, halo, OR^(as), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(K) is C₁₋₆ alkyl or H. In some embodiments,R^(K) is methyl. In some embodiments, R^(K) is H.

In some embodiments, R^(L) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(L) is C₁₋₆ alkyl or H. In some embodiments,R^(L) is methyl. In some embodiments, R^(L) is H.

In some embodiments, R^(M) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(M) is C₁₋₆ alkyl or H. In some embodiments,R^(M) is methyl. In some embodiments, R^(M) is H.

In some embodiments, R^(N) is H, halo, OR^(a5), C₁₋₆ alkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or C₆₋₁₀ aryl-C₁₋₄ alkyl isoptionally substituted with OR^(a5) or NR^(c5)R^(d5).

In some embodiments, R^(N) is C₁₋₆ alkyl or H. In some embodiments,R^(N) is methyl. In some embodiments, R^(N) is H.

In some embodiments, R^(K) and R^(M) together form a double bond betweenthe carbon atoms to which they are attached.

In some embodiments, R^(I) and R^(K) together form a double bond betweenthe carbon atoms to which they are attached In some embodiments, eachR^(X) is H or halo. In some embodiments, R^(X) is H. In someembodiments, R^(X) is F

In some embodiments, Y⁶ is C(═O), NR^(Y), or C(═O)NR^(Y).

In some embodiments, R^(Y) is H or C₁₋₄ alkyl. In some embodiments,R^(Y) is H. In some embodiments, R^(Y) is methyl.

In some embodiments, t1 is 0. In some embodiments, t1 is 1.

In some embodiments, t2 is 0. In some embodiments, t2 is 1.

In some embodiments, t3 is 0. In some embodiments, t3 is 1.

In some embodiments, u is 0. In some embodiments, u is 1. In someembodiments, u is 2.

In some embodiments, a is 0.

In some embodiments, v is 0. In some embodiments, v is 1.

In some embodiments, w is 0.

In some embodiments, w is 1.

In some embodiments, m is 0. In some embodiments, m is 1.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, q is 0. In some embodiments, q is 1.

In some embodiments, r is 1.

In other embodiments, provided herein is a compound of Formula I, or apharmaceutically acceptable salt thereof, having Formula IVa:

In other embodiments, provided herein is a compound of Formula I, or apharmaceutically acceptable salt thereof, having Formula IVb:

In other embodiments, provided herein is a compound of Formula I, or apharmaceutically acceptable salt thereof, having Formula IVc:

In other embodiments, provided herein is a compound of Formula I, or apharmaceutically acceptable salt thereof, having Formula IVd:

In other embodiments, provided herein is a compound of Formula I, or apharmaceutically acceptable salt thereof, having Formula IVe:

Crystalline5-[[(2S)-1-(3-Oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

In some embodiments, the compound of Formula I is5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(see Example 561). The compound of Example 561,5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one,can also be referred to as:

-   (S)-5-((1-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3    (2H)-one; or-   (S)-5-(1-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3    (2H)-one.

In some embodiments,5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneis crystalline and has the characteristics of Form A described below.The synthesis and characterization of5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one,including Form A, is described for example in Example 561.

In some embodiments, Form A has characteristic XRPD peaks selected fromabout 5.8, about 10.8, about 11.9, and about 17.2 degrees 2-theta. Insome embodiments, Form A has at least one characteristic XRPD peakselected from about 5.8, about 10.8, about 11.9, and about 17.2 degrees2-theta. In some embodiments, Form A has at least two characteristicXRPD peaks selected from about 5.8, about 10.8, about 11.9, and about17.2 degrees 2-theta. In some embodiments, Form A has a characteristicXRPD peak at about 5.8 degrees 2-theta. In some embodiments, Form A hasa characteristic XRPD peak at about 10.8 degrees 2-theta. In someembodiments, Form A has a characteristic XRPD peak at about 11.9 degrees2-theta. In some embodiments, Form A has a characteristic XRPD peak atabout 17.2 degrees 2-theta.

In some embodiments, Form A has at least one characteristic XRPD peakselected from about 5.8, about 10.8, about 11.9, about 13.3, about 13.5,about 15.5, and about 17.2 degrees 2-theta. In some embodiments, Form Ahas at least one characteristic XRPD peak selected from about 5.8, about10.8, about 11.2, about 11.9, about 12.3, about 13.3, about 13.5, about15.5, about 17.2, about 17.7, about 18.0, about 18.4, about 19.5, about21.0, and about 21.6 degrees 2-theta.

In some embodiments, Form A has at least two characteristic XRPD peaksselected from about 5.8, about 10.8, about 11.9, about 13.3, about 13.5,about 15.5, and about 17.2 degrees 2-theta. In some embodiments, Form Ahas at least two characteristic XRPD peaks selected from about 5.8,about 10.8, about 11.2, about 11.9, about 12.3, about 13.3, about 13.5,about 15.5, about 17.2, about 17.7, about 18.0, about 18.4, about 19.5,about 21.0, and about 21.6 degrees 2-theta.

In some embodiments, Form A has at least three characteristic XRPD peaksselected from about 5.8, about 10.8, about 11.9, about 13.3, about 13.5,about 15.5, and about 17.2 degrees 2-theta. In some embodiments, Form Ahas at least three characteristic XRPD peaks selected from about 5.8,about 10.8, about 11.2, about 11.9, about 12.3, about 13.3, about 13.5,about 15.5, about 17.2, about 17.7, about 18.0, about 18.4, about 19.5,about 21.0, and about 21.6 degrees 2-theta.

In some embodiments, Form A has at least four characteristic XRPD peaksselected from about 5.8, about 10.8, about 11.9, about 13.3, about 13.5,about 15.5, and about 17.2 degrees 2-theta. In some embodiments, Form Ahas at least four characteristic XRPD peaks selected from about 5.8,about 10.8, about 11.2, about 11.9, about 12.3, about 13.3, about 13.5,about 15.5, about 17.2, about 17.7, about 18.0, about 18.4, about 19.5,about 21.0, and about 21.6 degrees 2-theta.

In some embodiments, Form A has an XRPD pattern with characteristicpeaks as substantially shown in FIG. 8.

In some embodiments, Form A has an endotherm peak at a temperature ofabout 174° C. In some embodiments, Form A shows a weight loss of about0.5% when heated to about 150° C. In some embodiments, Form A has a DSCthermogram substantially as depicted in FIG. 9. In some embodiments,Form A has a TGA thermogram substantially as depicted in FIG. 9. In someembodiments, Form A has a DVS isotherm substantially as depicted in FIG.10.

In some embodiments, Form A has at least one characteristic XRPD peakselected from about 5.8, about 10.8, about 11.9, and about 17.2 degrees2-theta; and has an endotherm peak at a temperature of about 174° C. Insome embodiments, Form A has at least one characteristic XRPD peakselected from about 5.8, about 10.8, about 11.9, and about 17.2 degrees2-theta; and a DSC thermogram substantially as depicted in FIG. 9. Insome embodiments, Form A has at least one characteristic XRPD peakselected from about 5.8, about 10.8, about 11.9, and about 17.2 degrees2-theta; and a DVS isotherm substantially as depicted in FIG. 10.

In some embodiments, Form A can be isolated with a crystalline purity ofat least about 80%, about 85%, about 90%, about 95%, about 96%, about97%, about 98%, or about 99%. In some embodiments, Form A can beisolated with a crystalline purity greater than about 99%. In someembodiments, Form A can be isolated with a crystalline purity greaterthan about 99.9%. In some embodiments, Form A is substantially free ofother crystalline form. In some embodiments, Form A is substantiallyfree of amorphous form.

In some embodiments, provided is Form A prepared by precipitating5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-onefrom a solution comprising the compound and S1, wherein S1 is a solvent.In some embodiments, S1 is an organic solvent. In some embodiments, S1is selected from one of the following solvents: ethyl alcohol, methylisobutyl ketone, isopropyl acetate, methy t-butyl ether,2-methyltetrahydrofuran, 1,4-dioxane, toluene, acetone, dichloromethane,and water. In some embodiments, S1 is a mixture of organic solvents. Insome embodiments, S1 is a mixture of acetonitrile and heptane. In someembodiments, S1 is a mixture of isopropyl alcohol and ethyl acetate. Insome embodiments, S1 is a mixture of chloroform and ethyl acetate. Insome embodiments, S1 is a mixture of 1,4-dioxane and methanol. In someembodiments, S1 is a mixture of NMP and toluene. In some embodiments, S1is a mixture of petroleum ether and hexanes. In some embodiments, theprecipitating is carried out by concentration of the solution,evaporation of solvent, reduction of temperature of the solution,addition of anti-solvent, or combination thereof.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

At various places in the present specification various aryl, heteroaryl,cycloalkyl, and heterocycloalkyl rings are described. Unless otherwisespecified, these rings can be attached to the rest of the molecule atany ring member as permitted by valency. For example, the term“pyridinyl,” “pyridyl,” or “a pyridine ring” may refer to apyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

The term “n-membered,” where “n” is an integer, typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is “n”. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

For compounds of the invention in which a variable appears more thanonce, each variable can be a different moiety independently selectedfrom the group defining the variable. For example, where a structure isdescribed having two R groups that are simultaneously present on thesame compound, the two R groups can represent different moietiesindependently selected from the group defined for R.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted.

As used herein, the term “substituted” means that a hydrogen atom isreplaced by a non-hydrogen group. It is to be understood thatsubstitution at a given atom is limited by valency.

As used herein, the term “C_(i-j),” where i and j are integers, employedin combination with a chemical group, designates a range of the numberof carbon atoms in the chemical group with i-j defining the range. Forexample, C₁₋₆ alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6carbon atoms.

As used herein, the term “alkyl,” employed alone or in combination withother terms, refers to a saturated hydrocarbon group that may bestraight-chain or branched. In some embodiments, the alkyl groupcontains 1 to 7, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples ofalkyl moieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl, n-heptyl, and the like. In some embodiments, thealkyl group is methyl, ethyl, or propyl.

As used herein, “alkenyl,” employed alone or in combination with otherterms, refers to an alkyl group having one or more carbon-carbon doublebonds. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4carbon atoms. Example alkenyl groups include, but are not limited to,ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “alkynyl,” employed alone or in combination with otherterms, refers to an alkyl group having one or more carbon-carbon triplebonds. Example alkynyl groups include, but are not limited to, ethynyl,propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynylmoiety contains 2 to 6 or 2 to 4 carbon atoms.

As used herein, “halo” or “halogen”, employed alone or in combinationwith other terms, includes fluoro, chloro, bromo, and iodo. In someembodiments, halo is F or Cl.

As used herein, the term “haloalkyl,” employed alone or in combinationwith other terms, refers to an alkyl group having up to the full valencyof halogen atom substituents, which may either be the same or different.In some embodiments, the halogen atoms are fluoro atoms. In someembodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Examplehaloalkyl groups include CF₃, C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅, and thelike.

As used herein, the term “alkoxy,” employed alone or in combination withother terms, refers to a group of formula —O-alkyl. Example alkoxygroups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like. In some embodiments, the alkylgroup has 1 to 6 or 1 to 4 carbon atoms.

As used herein, “haloalkoxy,” employed alone or in combination withother terms, refers to a group of formula —O-(haloalkyl). In someembodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Anexample haloalkoxy group is —OCF₃.

As used herein, “amino,” employed alone or in combination with otherterms, refers to NH₂.

As used herein, the term “alkylamino,” employed alone or in combinationwith other terms, refers to a group of formula —NH(alkyl). In someembodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms.Example alkylamino groups include methylamino, ethylamino, propylamino(e.g., n-propylamino and isopropylamino), and the like.

As used herein, the term “dialkylamino,” employed alone or incombination with other terms, refers to a group of formula —N(alkyl)₂.Example dialkylamino groups include dimethylamino, diethylamino,dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and thelike. In some embodiments, each alkyl group independently has 1 to 6 or1 to 4 carbon atoms.

As used herein, the term “cycloalkyl,” employed alone or in combinationwith other terms, refers to a non-aromatic cyclic hydrocarbon includingcyclized alkyl and alkenyl groups.

Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3, or4 fused, bridged, or spiro rings) ring systems. Also included in thedefinition of cycloalkyl are moieties that have one or more aromaticrings (e.g., aryl or heteroaryl rings) fused (i.e., having a bond incommon with) to the cycloalkyl ring, for example, benzo derivatives ofcyclopentane, cyclohexene, cyclohexane, and the like, or pyridoderivatives of cyclopentane or cyclohexane. Ring-forming carbon atoms ofa cycloalkyl group can be optionally substituted by oxo. Cycloalkylgroups also include cycloalkylidenes. The term “cycloalkyl” alsoincludes bridgehead cycloalkyl groups (e.g., non-aromatic cyclichydrocarbon moieties containing at least one bridgehead carbon, such asadmantan-1-yl) and spirocycloalkyl groups (e.g., non-aromatichydrocarbon moieties containing at least two rings fused at a singlecarbon atom, such as spiro[2.5]octane and the like).

In some embodiments, the cycloalkyl group has 3 to 10 ring members, or 3to 7 ring members.

In some embodiments, the cycloalkyl group is monocyclic or bicyclic. Insome embodiments, the cycloalkyl group is monocyclic. In someembodiments, the cycloalkyl group is a C₃₋₇ monocyclic cycloalkyl group.Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,tetrahydronaphthalenyl, octahydronaphthalenyl, indanyl, and the like. Insome embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

As used herein, the term “cycloalkylalkyl,” employed alone or incombination with other terms, refers to a group of formulacycloalkyl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkylportion is methylene. In some embodiments, the cycloalkyl portion has 3to 10 ring members or 3 to 7 ring members. In some embodiments, thecycloalkyl group is monocyclic or bicyclic. In some embodiments, thecycloalkyl portion is monocyclic. In some embodiments, the cycloalkylportion is a C₃₋₇ monocyclic cycloalkyl group.

As used herein, the term “heterocycloalkyl,” employed alone or incombination with other terms, refers to a non-aromatic ring or ringsystem, which may optionally contain one or more alkenylene oralkynylene groups as part of the ring structure, which has at least oneheteroatom ring member independently selected from nitrogen, sulfur,oxygen, and phosphorus. Heterocycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused, bridged, or spiro rings) ringsystems. In some embodiments, the heterocycloalkyl group is a monocyclicor bicyclic group having 1, 2, 3, or 4 heteroatoms independentlyselected from nitrogen, sulfur and oxygen. Also included in thedefinition of heterocycloalkyl are moieties that have one or morearomatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having abond in common with) to the non-aromatic heterocycloalkyl ring, forexample, 1,2,3,4-tetrahydro-quinoline and the like.

Heterocycloalkyl groups can also include bridgehead heterocycloalkylgroups (e.g., a heterocycloalkyl moiety containing at least onebridgehead atom, such as azaadmantan-1-yl and the like) andspiroheterocycloalkyl groups (e.g., a heterocycloalkyl moiety containingat least two rings fused at a single atom, such as[1,4-dioxa-8-aza-spiro[4.5]decan-N-yl] and the like). In someembodiments, the heterocycloalkyl group has 3 to 10 ring-forming atoms,4 to 10 ring-forming atoms, or about 3 to 8 ring forming atoms. In someembodiments, the heterocycloalkyl group has 2 to 20 carbon atoms, 2 to15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8 carbon atoms. Insome embodiments, the heterocycloalkyl group has 1 to 5 heteroatoms, 1to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. The carbonatoms or heteroatoms in the ring(s) of the heterocycloalkyl group can beoxidized to form a carbonyl, an N-oxide, or a sulfonyl group (or otheroxidized linkage) or a nitrogen atom can be quaternized. In someembodiments, the heterocycloalkyl portion is a C₂₋₇ monocyclicheterocycloalkyl group. In some embodiments, the heterocycloalkyl groupis a morpholine ring, pyrrolidine ring, piperazine ring, piperidinering, tetrahydropyran ring, tetrahyropyridine, azetidine ring, ortetrahydrofuran ring.

As used herein, the term “heterocycloalkylalkyl,” employed alone or incombination with other terms, refers to a group of formulaheterocycloalkyl-alkyl-. In some embodiments, the alkyl portion has 1 to4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkylportion is methylene. In some embodiments, the heterocycloalkyl portionhas 3 to 10 ring members, 4 to 10 ring members, or 3 to 7 ring members.In some embodiments, the heterocycloalkyl group is monocyclic orbicyclic. In some embodiments, the heterocycloalkyl portion ismonocyclic. In some embodiments, the heterocycloalkyl portion is a C₂₋₇monocyclic heterocycloalkyl group.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to a monocyclic or polycyclic (e.g., a fused ringsystem) aromatic hydrocarbon moiety, such as, but not limited to,phenyl, 1-naphthyl, 2-naphthyl, and the like. In some embodiments, arylgroups have from 6 to 10 carbon atoms or 6 carbon atoms. In someembodiments, the aryl group is a monocyclic or bicyclic group. In someembodiments, the aryl group is phenyl or naphthyl.

As used herein, the term “arylalkyl,” employed alone or in combinationwith other terms, refers to a group of formula aryl-alkyl-. In someembodiments, the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbonatom(s). In some embodiments, the alkyl portion is methylene. In someembodiments, the aryl portion is phenyl. In some embodiments, the arylgroup is a monocyclic or bicyclic group. In some embodiments, thearylalkyl group is benzyl.

As used herein, the term “heteroaryl,” employed alone or in combinationwith other terms, refers to a monocyclic or polycyclic (e.g., a fusedring system) aromatic hydrocarbon moiety, having one or more heteroatomring members independently selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl group is a monocyclic or a bicyclicgroup having 1, 2, 3, or 4 heteroatoms independently selected fromnitrogen, sulfur and oxygen.

Example heteroaryl groups include, but are not limited to, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl,imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl,benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl,tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl,carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, azolyl, quinolinyl,isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl or the like. Thecarbon atoms or heteroatoms in the ring(s) of the heteroaryl group canbe oxidized to form a carbonyl, an N-oxide, or a sulfonyl group (orother oxidized linkage) or a nitrogen atom can be quaternized, providedthe aromatic nature of the ring is preserved. In some embodiments, theheteroaryl group has from 3 to 10 carbon atoms, from 3 to 8 carbonatoms, from 3 to 5 carbon atoms, from 1 to 5 carbon atoms, or from 5 to10 carbon atoms. In some embodiments, the heteroaryl group contains 3 to14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 ring-forming atoms. In someembodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2heteroatoms.

As used herein, the term “heteroarylalkyl,” employed alone or incombination with other terms, refers to a group of formulaheteroaryl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkylportion is methylene. In some embodiments, the heteroaryl portion is amonocyclic or bicyclic group having 1, 2, 3, or 4 heteroatomsindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl portion has 5 to 10 carbon atoms.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Geometric isomers of olefins,C═N double bonds, and the like can also be present in the compoundsdescribed herein, and all such stable isomers are contemplated in thepresent invention. Cis and trans geometric isomers of the compounds ofthe present invention may be isolated as a mixture of isomers or asseparated isomeric forms.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution. An example of tautomeric forms, pyridazin-3(2H)-one andpyridazin-3-ol, is depicted below:

Compounds of the invention also include all isotopes of atoms occurringin the intermediates or final compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. For example,isotopes of hydrogen include tritium and deuterium. In some embodiments,the compounds of the invention include at least one deuterium atom.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric iosomers, tautomers, and isotopes of thestructures depicted, unless otherwise specified.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,in the form of hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

As used herein, the term “crystalline” or “crystalline form” refers to acrystalline solid form of a chemical compound, including, but notlimited to, a single-component or multiple-component crystal form, e.g.,including solvates, hydrates, clathrates, and co-crystals. As usedherein, “crystalline form” is meant to refer to a certain latticeconfiguration of a crystalline substance. Different crystalline forms ofthe same substance typically have different crystalline lattices (e.g.,unit cells) which are attributed to different physical properties thatare characteristic of each of the crystalline forms. In some instances,different lattice configurations have different water or solventcontent. The different crystalline lattices can be identified by solidstate characterization methods such as by X-ray powder diffraction(XRPD). Other characterization methods such as differential scanningcalorimetry (DSC), thermogravimetric analysis (TGA), dynamic vaporsorption (DVS), solid state NMR, and the like further help identify thecrystalline form as well as help determine stability and solvent/watercontent.

Crystalline forms of a substance include both solvated (e.g., hydrated)and non-solvated (e.g., anhydrous) forms. A hydrated form is acrystalline form that includes water in the crystalline lattice.Hydrated forms can be stoichiometric hydrates, where the water ispresent in the lattice in a certain water/molecule ratio such as forhemihydrates, monohydrates, dihydrates, etc. Hydrated forms can also benon-stoichiometric, where the water content is variable and dependent onexternal conditions such as humidity.

As used herein, the term “substantially crystalline,” means a majorityof the weight of a sample or preparation of a salt (or hydrate orsolvate thereof) of the invention is crystalline and the remainder ofthe sample is a non-crystalline form (e.g., amorphous form) of the samecompound. In some embodiments, a substantially crystalline sample has atleast about 95% crystallinity (e.g., about 5% of the non-crystallineform of the same compound), preferably at least about 96% crystallinity(e.g., about 4% of the non-crystalline form of the same compound), morepreferably at least about 97% crystallinity (e.g., about 3% of thenon-crystalline form of the same compound), even more preferably atleast about 98% crystallinity (e.g., about 2% of the non-crystallineform of the same compound), still more preferably at least about 99%crystallinity (e.g., about 1% of the non-crystalline form of the samecompound), and most preferably about 100% crystallinity (e.g., about 0%of the non-crystalline form of the same compound). In some embodiments,the term “fully crystalline” means at least about 99% or about 100%crystallinity.

Crystalline forms are most commonly characterized by XRPD. An XRPDpattern of reflections (peaks) is typically considered a fingerprint ofa particular crystalline form. It is well known that the relativeintensities of the XRPD peaks can widely vary depending on, inter alia,the sample preparation technique, crystal size distribution, filters,the sample mounting procedure, and the particular instrument employed.In some instances, new peaks may be observed or existing peaks maydisappear, depending on the type of instrument or the settings (forexample, whether a Ni filter is used or not). As used herein, the term“peak” refers to a reflection having a relative height/intensity of atleast about 4% of the maximum peak height/intensity. Moreover,instrument variation and other factors can affect the 2-theta values.Thus, peak assignments, such as those reported herein, can vary by plusor minus about 0.2° (2-theta), and the term “substantially” as used inthe context of XRPD herein is meant to encompass the above-mentionedvariations.

In the same way, temperature readings in connection with DSC, TGA, orother thermal experiments can vary about +3° C. depending on theinstrument, particular settings, sample preparation, etc. For example,with DSC it is known that the temperatures observed will depend on therate of the temperature change as well as the sample preparationtechnique and the particular instrument employed. Thus, the valuesreported herein related to DSC thermograms can vary, as indicated above,by +3° C. Accordingly, a crystalline form reported herein having a DSCthermogram “substantially” as shown in any of the Figures is understoodto accommodate such variation.

As used herein, and unless otherwise specified, the term “about”, whenused in connection with a numeric value or range of values which isprovided to describe a particular solid form (e.g., a specifictemperature or temperature range, such as describing a melting,dehydration, or glass transition; a mass change, such as a mass changeas a function of temperature or humidity; a solvent or water content, interms of, for example, mass or a percentage; or a peak position, such asin analysis by, for example, ¹³C NMR, DSC, TGA and XRPD), indicate thatthe value or range of values may deviate to an extent deemed reasonableto one of ordinary skill in the art while still describing theparticular solid form.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the non-toxic salts ofthe parent compound formed, for example, from non-toxic inorganic ororganic acids. The pharmaceutically acceptable salts of the presentinvention can be synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal ofPharmaceutical Science, 66, 2 (1977), each of which is incorporatedherein by reference in its entirety.

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons,Inc., New York (1999), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), ormass spectrometry, or by chromatography such as high performance liquidchromatography (HPLC) or thin layer chromatography.

The expressions, “ambient temperature,” “room temperature,” and “RT”, asused herein, are understood in the art, and refer generally to atemperature, e.g. a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Compounds of Formula I can be prepared according to numerous preparatoryroutes known in the literature. Example synthetic methods for preparingcompounds of the invention are provided in the Schemes below. Unlessnoted otherwise, all substituents are as defined herein.

In the process depicted in Scheme 1, an appropriately substituted,halogen containing compound (i.e., X^(a)=Cl or Br) of Formula (1-1) isprotected as the 2-(trimethylsilyl)ethoxymethyl ether (“SEM”) compoundof Formula (1-2) by treatment with 2-(trimethylsilyl)ethoxymethylchloride (“SEM-Cl”) in the presence of sodium hydride (NaH).

Compound of Formula (1-2) can be reacted with a variety of nucleophilesto provide compounds of Formula (I) following deprotection of the SEMprotecting group, as shown in Schemes 2-4.

In the process depicted in Scheme 2, the compound of Formula (1-2)(wherein Y^(a) is O, NR^(Y), or S) is reacted with a compound havingFormula (1-3) in the presence of a base (e.g., triethylamine or Cs₂CO₃)to provide a compound of formula (1-4). Deprotection with an acid (e.g.,trifluoroacetic acid or hydrochloric acid) provides a compound ofFormula (IA).

In the process depicted in Scheme 3, the compound of Formula (1-2) isreacted with a compound having Formula (1-5) in the presence of a base(e.g., triethylamine or Cs₂CO₃) to provide a compound of Formula (1-6).Deprotection with an acid (e.g., trifluoroacetic acid or hydrochloricacid) provides a compound of Formula (IB).

In the process depicted in Scheme 4, the compound of Formula (1-2) isreacted with a compound having Formula (1-7) in the presence of a base(e.g., triethylamine or Cs₂CO₃) to provide a compound of Formula (1-8).Deprotection with an acid (e.g., trifluoroacetic acid or hydrochloricacid) provides a compound of Formula (IC).

Methods of Use

Compounds of the invention can inhibit the activity of PARP7. Forexample, the compounds of the invention can be used to inhibit activityof PARP7 in a cell or in an individual or patient in need of inhibitionof the enzyme by administering an inhibiting amount of a compound of theinvention to the cell, individual, or patient.

As PARP7 inhibitors, the compounds of the invention are useful in thetreatment of various diseases associated with abnormal expression oractivity of PARP7. For example, the compounds of the invention areuseful in the treatment of cancer. In some embodiments, the cancerstreatable according to the present invention include breast, centralnervous system, endometrium, kidney, large intestine, lung, oesophagus,ovary, pancreas, prostate, stomach, head and neck (upper aerodigestive),urinary tract, colon, and others.

In some embodiments, the cancers treatable according to the presentinvention include hematopoietic malignancies such as leukemia andlymphoma. Example lymphomas include Hodgkin's or non-Hodgkin's lymphoma,multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma(DLBCL)), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, hairycell lymphoma, and Burkett's lymphoma. Example leukemias include acutelymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chroniclymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML).

Other cancers treatable by the administration of the compounds of theinvention include liver cancer (e.g., hepatocellular carcinoma), bladdercancer, bone cancer, glioma, breast cancer, cervical cancer, coloncancer, endometrial cancer, epithelial cancer, esophageal cancer,Ewing's sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer,gastrointestinal tumors, head and neck cancer (upper aerodigestivecancer), intestinal cancers, Kaposi's sarcoma, kidney cancer, laryngealcancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer,prostate cancer, rectal cancer, skin cancer, stomach cancer, testicularcancer, thyroid cancer, and uterine cancer.

In some embodiments, the cancer treatable by administration of thecompounds of the invention is multiple myeloma, DLBCL, hepatocellularcarcinoma, bladder cancer, esophageal cancer, head and neck cancer(upper aerodigestive cancer), kidney cancer, prostate cancer, rectalcancer, stomach cancer, thyroid cancer, uterine cancer, and breastcancer.

The PARP7 inhibitors of the invention may also have therapeutic utilityin PARP7-related disorders in disease areas such as cardiology,virology, neurodegeneration, inflammation, and pain, particularly wherethe diseases are characterized by overexpression or increased activityof PARP7.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” PARP7 or “contacting” a cell with a compound ofthe invention includes the administration of a compound of the presentinvention to an individual or patient, such as a human, having PARP7, aswell as, for example, introducing a compound of the invention into asample containing a cellular or purified preparation containing PARP7.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to mammals, and particularly humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician.

As used herein the term “treating” or “treatment” refers to 1)inhibiting the disease in an individual who is experiencing ordisplaying the pathology or symptomatology of the disease (i.e.,arresting further development of the pathology and/or symptomatology),or 2) ameliorating the disease in an individual who is experiencing ordisplaying the pathology or symptomatology of the disease (i.e.,reversing the pathology and/or symptomatology).

As used herein the term “preventing” or “prevention” refers topreventing the disease in an individual who may be predisposed to thedisease but does not yet experience or display the pathology orsymptomatology of the disease.

Combination Therapy

One or more additional pharmaceutical agents or treatment methods suchas, for example, chemotherapeutics or other anti-cancer agents, immuneenhancers, immunosuppressants, immunotherapies, radiation, anti-tumorand anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.),and/or kinase (tyrosine or serine/threonine), epigenetic or signaltransduction inhibitors can be used in combination with the compounds ofthe present invention. The agents can be combined with the presentcompounds in a single dosage form, or the agents can be administeredsimultaneously or sequentially as separate dosage forms.

Suitable agents for use in combination with the compounds of the presentinvention for the treatment of cancer include chemotherapeutic agents,targeted cancer therapies, immunotherapies or radiation therapy.Compounds of this invention may be effective in combination withanti-hormonal agents for treatment of breast cancer and other tumors.Suitable examples are anti-estrogen agents including but not limited totamoxifen and toremifene, aromatase inhibitors including but not limitedto letrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g.prednisone), progestins (e.g. megastrol acetate), and estrogen receptorantagonists (e.g. fulvestrant). Suitable anti-hormone agents used fortreatment of prostate and other cancers may also be combined withcompounds of the present invention. These include anti-androgensincluding but not limited to flutamide, bicalutamide, and nilutamide,luteinizing hormone-releasing hormone (LHRH) analogs includingleuprolide, goserelin, triptorelin, and histrelin, LHRH antagonists(e.g. degarelix), androgen receptor blockers (e.g. enzalutamide) andagents that inhibit androgen production (e.g. abiraterone).

Angiogenesis inhibitors may be efficacious in some tumors in combinationwith FGFR inhibitors. These include antibodies against VEGF or VEGFR orkinase inhibitors of VEGFR. Antibodies or other therapeutic proteinsagainst VEGF include bevacizumab and aflibercept. Inhibitors of VEGFRkinases and other anti-angiogenesis inhibitors include but are notlimited to sunitinib, sorafenib, axitinib, cediranib, pazopanib,regorafenib, brivanib, and vandetanib

Suitable chemotherapeutic or other anti-cancer agents include, forexample, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide(Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman,triethylene-melamine, triethylenethiophosphoramine, busulfan,carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

Other anti-cancer agent(s) include antibody therapeutics to checkpointor costimulatory molecules such as CTLA-4, PD-1, PD-L1 or 4-1BB,respectively, or antibodies to cytokines (IL-10, TGF-β, etc.). Exemplarycancer immunotherapy antibodies include pembrolizumab, ipilimumab,nivolumab, atezolizumab and durvalumab. Additional anti-cancer agent(s)include antibody therapeutics directed to surface molecules ofhematological cancers such as ofatumumab, rituximab and alemtuzumab.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Apharmaceutical composition refers to a combination of a compound of theinvention, or its pharmaceutically acceptable salt, and at least onepharmaceutically acceptable carrier. These compositions can be preparedin a manner well known in the pharmaceutical art, and can beadministered by a variety of routes, depending upon whether local orsystemic treatment is desired and upon the area to be treated.Administration may be oral, topical (including ophthalmic and to mucousmembranes including intranasal, vaginal and rectal delivery), pulmonary(e.g., by inhalation or insufflation of powders or aerosols, includingby nebulizer; intratracheal, intranasal, epidermal and transdermal),ocular, or parenteral.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of the inventionabove in combination with one or more pharmaceutically acceptablecarriers. In making the compositions of the invention, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

The compositions can be formulated in a unit dosage form. The term “unitdosage form” refers to a physically discrete unit suitable as unitarydosages for human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpre-formulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepre-formulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid pre-formulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration.

The therapeutic dosage of the compounds of the present invention canvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. The proportion or concentration of a compound of theinvention in a pharmaceutical composition can vary depending upon anumber of factors including dosage, chemical characteristics (e.g.,hydrophobicity), and the route of administration. For example, thecompounds of the invention can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral administration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extent of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

The compounds of the invention can also be formulated in combinationwith one or more additional active ingredients which can include anypharmaceutical agent such as anti-viral agents, anti-cancer agents,vaccines, antibodies, immune enhancers, immune suppressants,anti-inflammatory agents and the like.

EXAMPLES

Equipment:

¹H NMR Spectra were recorded at 300 or 400 MHz using a Bruker AVANCE 300MHz/400 MHz spectrometer. NMR interpretation was performed using BrukerTopspin software to assign chemical shift and multiplicity. In caseswhere two adjacent peaks of equal or unequal height were observed, thesetwo peaks may be labeled as either a multiplet or as a doublet. In thecase of a doublet, a coupling constant using this software may beassigned. In any given example, one or more protons may not be observeddue to obscurity by water and/or solvent peaks. LCMS equipment andconditions are as follows:

-   -   1. LC (basic condition): Shimadzu LC-20AD, Binary Pump, Diode        Array Detector. Column: Kinetex 2.6 m EVO C18 100 A, 50*3.0 mm,        2.6 um. Mobile phase: A: Water/5 mM NH₄HCO₃, B: Acetonitrile.        Flow Rate: 1.2 mL/min at 40° C. Detector: 254 nm, 220 nm.        Gradient stop time, 2.9 min. Timetable:

T (min) A (%) B (%) 0.01 90 10 2.10 5 95 2.70 5 95 2.90 90 10

-   -   2. LC (acidic condition): Shimadzu LC-20AD, Binary Pump, Diode        Array Detector. Column: Ascentis Express C18, 50*3.0 mm, 2.7 um.        Mobile phase: A: Water/0.05% TFA, B: Acetonitrile/0.05% TFA.        Flow Rate: 1.5 mL/min at 40° C. Detector: 254 nm, 220 nm.        Gradient stop time, 2.9 min. Timetable:

T (min) A (%) B (%) 0.01 90 5 2.10 5 95 2.70 5 95 2.90 90 5

-   -   1. S:LCMS-2020, Quadrupole LC/MS, Ion Source: ES-API, TIC:        90˜900 m/z, Fragmentor: 60, Drying gas flow: 15 L/min,        Nebulizing Gas Flow: 1.5 L/min, Drying gas temperature: 250° C.,        Vcap: 1100V    -   2. Sample preparation: samples were dissolved in ACN or methanol        at 1-10 mg/mL, then filtered through a 0.22 μm filter membrane.        Injection volume: 1˜10 μL.

XRPD Analysis:

For XRPD analysis, PANalytical Empyrean/X' Pert3 X-ray powderdiffractometers were used. The XRPD parameters used are listed below:

XRPD Parameters CPE-026 (Reflection CPE-135 (Reflection CPE-221(Reflection Parameters Mode) Mode) Mode) Model Empyrean X′ Pert3 X′Pert3 X-Ray Cu, kα, Cu, kα, Cu, kα, wavelength Kα1 (Å): 1.540598, Kα1(Å): 1.540598, Kα1 (Å): 1.540598, Kα2 (Å): 1.544426 Kα2 (Å): 1.544426Kα2 (Å): 1.544426 Kα2/Kα1 intensity Kα2/Kα1 intensity Kα2/Kα1 intensityratio: 0.50 ratio: 0.50 ratio: 0.50 X-Ray tube 45 kV, 40 mA 45 kV, 40 mA45 kV, 40 mA setting Divergence slit Automatic ⅛° ⅛° Scan modeContinuous Continuous Continuous Scan range 3°~40° 3°~40° 3°~40° (2θ/°)Step size (2θ/°)  0.0167  0.0263  0.0263 Scan step time 17.780 46.66539.525 (s) Test time (s) 5 min 30 s 5 min 04 s 4 min 27 sThe term “2Th” refers to 2-theta. The term “FWIM” refers to full widthat half maximum. The term “rel. int.” refers to relative intensity.

DSC/TGA Analysis:

TGA data were collected using a TA Q5000/Q5500 TGA from TA Instruments.DSC was performed using a TA Q2000/Q2500 DSC from TA Instruments.Detailed parameters used are listed below:

Parameters for TGA and DSC Parameters TGA DSC Method Ramp Ramp Samplepan Aluminum, open Aluminum, crimped Temperature RT - desiredtemperature 25° C. - desired temperature Heating rate 10° C./min 10°C./min Purge gas N₂ N₂

DVS Analysis:

DVS was measured via a SMS (Surface Measurement Systems) DVS Intrinsic.The relative humidity at 25° C. were calibrated against deliquescencepoint of LiCl, Mg(NO₃)₂ and KCl. Parameters for DVS test are listedbelow:

Parameters for DVS test Parameters DVS Temperature 25° C. Sample size10~20 mg Gas and flow rate N₂, 200 mL/min dm/dt 0.002%/min Min. dm/dtstability duration 10 min Max. equilibrium time 180 min RH range 95%RH-0% RH-95% RH RH step size 10% (90% RH-0% RH-90% RH) 5% (95% RH-90% RHand 90% RH-95% RH) RH = relative humidity. dm/dt = rate of change inmoisture content over time.

Definitions

ACN (acetonitrile); Ac₂O (acetic anhydride); AIBN(2,2′-azobis(2-methylpropionitrile); BHMPO(N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide); Boc(tert-butoxycarbonyl); Boc₂O (di-tert-butyl dicarbonate); CAN (cerium(IV) ammonium nitrate); CsF (cesium fluoride); CuI (copper iodide); CCl₄(carbon tetrachloride); CH₃CN (acetonitrile); CDCl₃ (deuteratedchloroform); CD₃OD (deuterated methanol); Cu(acac)₂ (copper(II)acetylacetonate); Dess Martin(1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one); DBU(1,8-diazabicyclo[5.4.0]undec-7-ene); DCM (dichloromethane); DEA(diethylamine); DEAD (diethyl azodicarboxylate); DIAD (diisopropylazodicarboxylate); DIPEA (N,N-diisopropylethylamine); DMF(N,N-dimethylformamide); DMAP (4-dimethyl aminopyridine); DMSO(dimethylsulfoxide); DMSO-d₆ (deuterated dimethylsulfoxide); DPPA(diphenylphosphoryl azide); eq (equivalent); EDCl(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); EtOAc (ethyl acetate);EtOH (ethanol); g (gram); h (hour); Grubbs 2nd generation catalyst(1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium;(HATU(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate); HOBT (hydroxybenzotriazole); ¹H NMR(proton nuclear magnetic resonance); HCl (hydrochloric acid); Hz(hertz); IPA (iso-propyl alcohol); K₂CO₃ (potassium carbonate); L(litre); LiCl (lithium chloride); LCMS (liquid chromatography-massspectrometry); M (molar); MeOH (methanol); mg (milligrams); MHz(megahertz); min (minutes); MtBE (methyl tert-butyl ether); mL(milliliters), mmol (millimoles); Ms₂O (methanesulfonic anhydride); NaCl(sodium chloride); NaH (sodium hydride); NaHMDS (sodiumbis(trimethylsilyl)amide); NH₄Cl (ammonium chloride); NaN₃ (sodiumazide); NBS (N-bromo succinimide); NMP (N-methyl-2-pyrrolidone);Pd(allyl)Cl₂ (Bis(η3-allyl)di(μ-chloro)dipalladium(II)); Pd(dppf)Cl₂([1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)); prep-HPLC(preparative high-performance liquid chromatography); ppm (parts permillion); PMB (4-methoxy benzyl); Rockphos(2-Di(tert-butyl)phosphino-2,4,6′-triisopropyl-3-methoxy-6-methylbiphenyl));RT (room temperature); SEM (2-(trimethylsilyl)ethoxymethyl); SEMCl(2-(trimethylsilyl)ethoxymethyl chloride); TBAF (tetrabutyl ammoniumfluoride); TEA (triethyl amine); THF (tetrahydrofuran); TsCl (tosylchloride); tR (retention time); T3P (1-propanephosphonic anhydride);TfOH (trifluoromethanesulfonic acid); TFA (trifluoroacetic acid); TLC(thin layer chromatography); TMSI (iodotrimethyl silane); v/v(volume/volume).

Synthesis of Intermediates Int-A1:2-(Piperazin-1-yl)pyrimidine-5-carbonitrile Dihydrochloride

Step 1: Tert-butyl 4-(5-cyanopyrimidin-2-yl)piperazine-1-carboxylate

A solution of 2-chloropyrimidine-5-carbonitrile (5 g, 35.83 mmol, 1equiv), tert-butyl piperazine-1-carboxylate (6.7 g, 35.97 mmol, 1.00equiv) and K₂CO₃ (9.9 g, 71.63 mmol, 2.00 equiv) in NMP (80 mL) wasstirred for 1 h at 80° C. The resulting mixture was diluted with 1 L ofwater, and the solids were collected by filtration and dried by oven toafford 8.4 g of the title compound as a white solid. LCMS: [M+H]⁺290.15.

Step 2: 2-(Piperazin-1-yl)pyrimidine-5-carbonitrile Dihydrochloride

A solution of tert-butyl4-(5-cyanopyrimidin-2-yl)piperazine-1-carboxylate (8.4 g, 29.03 mmol, 1equiv) in HCl/dioxane (40 mL, 4M) was stirred for 1 h at RT, and thenthe resulting solution was concentrated under vacuum to afford 6.4 g(76%) of the title compound as a white solid. LCMS: [M+H]⁺ 190.10.

Int-A2: 2-(Piperazin-1-yl)-5-(trifluoromethyl)pyrimidine Dihydrochloride

Step 1: Tert-butyl4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxylate

A solution of 2-chloro-5-(trifluoromethyl)pyrimidine (100 g, 550 mmol,1.05 equiv), tert-butyl piperazine-1-carboxylate (96.7 g, 520 mmol, 1equiv), and K₂CO₃ (151.8 g, 1100 mmol, 2 equiv) in NMP (800 mL) wasstirred for 1 h at 80° C. followed by the addition of 2.5 L of H₂O. Thesolids were collected by filtration to afford 190 g (94%) of the titlecompound as a white solid. LCMS: [M+H]⁺ 333.16.

Step 2: 2-(Piperazin-1-yl)-5-(trifluoromethyl)pyrimidine

A solution of tert-butyl4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxylate (190 g,571.73 mmol, 1 equiv) in HCl/dioxane (800 mL/4M) was stirred for 1 h atRT. The solids were collected by filtration to afford 154 g (99%) of thetitle compound as a white solid. LCMS: [M+H]⁺ 199.08.

Int-A3: 5-Chloro-2-(piperazin-1-yl)pyrimidine Dihydrochloride

Step 1: Tert-butyl 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate

A solution of 2,5-dichloropyrimidine (19.4 g, 13.00 mmol, 1.05 equiv),tert-butyl piperazine-1-carboxylate (23 g, 12.40 mmol, 1 equiv), andK₂CO₃ (34 g, 25.00 mmol, 2 equiv) in NMP (500 mL) was stirred for 1 h at80° C. followed by the addition of 600 mL of H₂O which was added to theresulting solution. The solids were collected by filtration to afford 41g crude of the title compound as a white solid. LCMS: [M+H]⁺ 299.13.

Step 2: 5-Chloro-2-(piperazin-1-yl)pyrimidine Dihydrochloride

A solution of tert-butyl4-(5-chloropyrimidin-2-yl)piperazine-1-carboxylate (41 g, 14.00 mmol, 1equiv) in HCl/dioxane (500 mL/4M) was stirred for 1 h at RT. The solidswere collected by filtration to afford 26.7 g of the title compound as awhite solid. LCMS: [M+H]⁺ 199.08.

Int-A4: 6-(Piperazin-1-yl)pyridine-3-carbonitrile Dihydrochloride

Step 1: Tert-butyl 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate

A solution of 6-chloropyridine-3-carbonitrile (90 g, 650 mmol, 1.05equiv), tert-butyl piperazine-1-carboxylate (114.3 g, 620 mmol, 1equiv), and K₂CO₃ (171.1 g, 124 mmol, 2 equiv) in NMP (500 mL) wasstirred for 1 h at 80° C. followed by the addition of 1.5 L of H₂O whichwas added to the resulting solution. The solids were collected byfiltration to afford 195 g of title compound as a white solid. LCMS:[M+H]⁺ 289.17.

Step 2: 6-(Piperazin-1-yl)pyridine-3-carbonitrile Dihydrochloride

Tert-butyl 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate (195 g, 680mmol, 1 equiv) and HCl/dioxane (800 mL/4M) was stirred for 1 h at RT.The solids were collected by filtration to afford 160 g of the titlecompound as a white solid. LCMS: [M+H]⁺ 189.12.

Int-A5: 1-(5-Chloropyridin-2-yl)piperazine Dihydrochloride

Step 1: Tert-butyl 4-(5-chloropyridin-2-yl)piperazine-1-carboxylate

A solution of tert-butyl piperazine-1-carboxylate (10 g, 53.69 mmol,1.00 equiv), NMP (30 mL), potassium carbonate (13.4 g, 96.95 mmol, 1.80equiv), and 2,5-dichloropyridine (8.7 g, 58.79 mmol, 1.10 equiv) wasstirred for 20 h at 110° C. To the reaction mixture was then added 500mL of H₂O. The solids were collected by filtration to afford 10.2 g(64%) of the title compound as a light yellow solid. LCMS: [M+H]⁺298.12.

Step 2: 1-(5-Chloropyridin-2-yl)piperazine Dihydrochloride

A solution of tert-butyl4-(5-chloropyridin-2-yl)piperazine-1-carboxylate (10.2 g, 34.25 mmol,1.00 equiv) and HCl/dioxane (50 mL/4M) was stirred for 1 h at RT. Thesolids were collected by filtration to afford 7.4 g (800%) of the titlecompound as a light yellow solid. LCMS: [M+H]⁺ 198.07.

Int-A6:5-Chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one

Step 1:4,5-Dibromo-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

To a solution of 4,5-dibromo-2,3-dihydropyridazin-3-one (3500 g, 13.78mol, 1.00 equiv) in DMF (30 L) was added sodium hydride (400 g, 16.56mol, 1.20 equiv) in batches at 0° C. under nitrogen. The resultingsolution was stirred for 1 h at RT followed by addition of[2-(chloromethoxy)ethyl]trimethylsilane (2500 g, 15.2 mol, 1.10 equiv)dropwise at 0° C. The reaction mixture was stirred for 2 h at RT. Thereaction was then quenched by the addition of 30 L of water. Theresulting solution was extracted with 3×50 L of EtOAc and the organiclayers combined. The organic layers were washed with 3×30 L of brine,dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford 4.2 kg of title compound. LCMS: [M+H]⁺ 384.70.

Step 2:4-Bromo-5-chloro-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

To a solution of4,5-dibromo-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(2200 g, 5.73 mol, 1.00 equiv) in NMP (6 L) was added chlorolithium (231g, 5.73 mol, 1.00 equiv) and the resulting solution was stirred for 4 hat 95° C. This reaction was repeated again with a 2000 g scale batch.After completion, the two batch reactions were combined and then dilutedby the addition of 10 L of water, extracted with 3×20 L of EtOAc and theorganic layers combined. The organic layers were washed with 3×20 L ofbrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by column chromatography(EtOAc:petroleum ether, 1:50, v/v). In total, from 4.2 kg of4,5-dibromo-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-onematerial starting material, 2.2 kg (59% yield) of title compound wasobtained. LCMS: [M+H]⁺ 340.90.

Step 3:5-Chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

To a solution of4-bromo-5-chloro-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1100 g, 3.23 mol, 1.00 equiv) in NMP (6 L) at RT was added CuI (56 g,0.64 mol, 0.20 equiv) followed by dropwise addition of methyl2,2-difluoro-2-(fluorosulfonyl)acetate (1865 g, 9.7 mol, 3.00 equiv).The resulting solution was stirred for 2 h at 80° C. The reaction wasthen quenched by the addition of 10 L of water and extracted with 3×10 Lof EtOAc. The organic layers were combined and washed with 3×10 L ofbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by column chromatography(EtOAc/petroleum ether, 1/100, v/v) to afford 1030 g (76%) of the titlecompound. LCMS: [M+H]⁺ 329.00. ¹H NMR (300 MHz, CDCl₃) δ 7.82 (s, 1H),5.50 (d, J=27.3 Hz, 2H), 3.74 (dt, J=12.9, 8.2 Hz, 2H), 0.97 (td, J=8.3,5.0 Hz, 2H), 0.01 (d, J=2.1 Hz, 9H).

Int-A7:4,5-Dichloro-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of 4,5-dichloro-2,3-dihydropyridazin-3-one (10 g, 60.62 mmol,1 equiv) in DMF (40 mL) was stirred at 0° C. and NaH (2.9 g, 121.23mmol, 2 equiv) was added at 0° C. in several batches. The mixture wasstirred for 30 min at 0° C. followed by the addition of[2-(chloromethoxy)ethyl]trimethylsilane (13 g, 78.80 mmol, 1.3 equiv)slowly at 0° C. The resulting solution was stirred for an additional 10min at 0° C. The reaction was then quenched by the addition of 100 mL ofwater. The resulting solution was extracted with 2×80 mL of EtOAc andthe organic layers combined. The resulting solution was extracted with3×60 mL of NaCl (aq) and the organic layers combined and concentratedunder vacuum. The residue was applied onto a silica gel column elutingwith EtOAc/petroleum ether (4/96) to afford 9 g (50%) of the titlecompound as a yellow oil. LCMS: [M−Cl]⁺295.04.

Int-A8:4,5-Dibromo-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

To a solution of 4,5-dibromo-2,3-dihydropyridazin-3-one (3500 g, 13.78mol, 1.00 equiv) in DMF (30 L) was added NaH (400 g, 16.56 mol, 1.20equiv) in batches at 0° C. under nitrogen. The resulting solution wasstirred for 1 h at RT, then dropwise2-(chloromethoxy)ethyl]trimethylsilane (2500 g, 15.2 mol, 1.10 equiv)was added at 0° C. and stirred for 2 h at RT. The reaction was thenquenched by the addition of 30 L of water. The resulting solution wasextracted with 3×50 L of EtOAc and the organic layers combined. Theorganic layers were washed with 3×30 L of brine, dried over anhydroussodium sulfate and concentrated under vacuum to afford 4.2 kg of titlecompound. LCMS: [M+H]⁺ 384.70.

Int-A9:3-[2-[(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoicAcid

Step 1: Tert-butyl3-[2-[(5-chloro-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate

A solution of tert-butyl 3-(2-hydroxyethoxy)propanoate (778.8 mg, 4.09mmol, 1.00 equiv), Cs₂CO₃ (2.66 g, 8.16 mmol, 2.00 equiv), and4,5-dichloro-2-[2-(trimethylsilyl)ethoxy]methyl-2,3-dihydropyridazin-3-one(1.2 g, 4.06 mmol, 1.00 equiv) in ACN (15 mL) was stirred for 3 h at 80°C. The solids were filtered and the resulting mixture was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography with EtOAc/petroleum ether (1:1) to afford 200 mg (11%)of title compound as a white solid. LCMS: [M+H]⁺ 449.01.

Step 2:3-[2-[(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoicAcid

A solution of tert-butyl3-[2-[(5-chloro-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate(10 mg, 0.02 mmol, 1.00 equiv) in TFA (2 mL) and DCM (10 mL) was stirredfor 0.5 h at RT. After completion, the crude product was directlyconcentrated under reduced pressure to afford 776 mg of title compoundas a white solid. LCMS: [M+H]⁺ 263.01.

Int-A10:3-[2-[(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)amino]ethoxy]propanoicAcid

Step 1: Methyl 3-(2-(tert-butoxycarbonylamino)ethoxy)propanoate

A solution of tert-butyl N-(2-hydroxyethyl)carbamate (6 g, 37.2 mmol,1.00 equiv), sodium hydride (2 g, 83.3 mmol, 1.50 equiv), methyl3-bromopropanoate (6.18 g, 37.0 mmol, 1.00 equiv) in THF (40 mL) wasstirred overnight at 25° C. The resulting mixture was concentrated underreduced pressure and the residue was purified by silica gel columnchromatography eluting with EtOAc/petroleum ether (1:3, v:v) to afford1.6 g (17%) of title compound as a colorless oil. LCMS: [M+H]⁺ 248.14.

Step 2: Methyl 3-(2-aminoethoxy)propanoate Hydrochloride

A solution of 3 methyl3-(2-[[(tert-butoxy)carbonyl]amino]ethoxy)propanoate (1.6 g, 6.47 mmol,1.00 equiv) in HCl/dioxane (20 mL/4M) was stirred for 1 h at 25° C. Theresulting mixture was concentrated under vacuum to afford 900 mg (95%)of title compound as a colorless oil. LCMS: [M+H]⁺ 148.09.

Step 3: Methyl3-[2-[(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)amino]ethoxy]propanoate

A solution of methyl 3-(2-aminoethoxy)propanoate (955 mg, 6.5 mmol, 1.00equiv), 4,5-dichloro-2,3-dihydropyridazin-3-one (1.06 g, 6.43 mmol, 1.00equiv), and TEA (1.95 g, 19.3 mmol, 3.00 equiv) in EtOH (20 mL) wasstirred overnight at 80° C. The resulting mixture was concentrated underreduced pressure and purified by silica gel column chromatographyeluting with EtOAc/petroleum ether (3:1) to afford 1.2 g (67%) of titlecompound as a yellow oil. LCMS: [M+H]⁺ 276.07.

Step 4:3-[2-[(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)amino]ethoxy]propanoicAcid

A solution of methyl3-[2-[(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)amino]ethoxy]propanoate(1.2 g, 4.35 mmol, 1.00 equiv) and LiOH.H₂O (488 mg, 11.6 mmol, 2.00equiv) in water (50 mL) and MeOH (50 mL) was stirred overnight at 50° C.The resulting mixture was concentrated under reduced pressure to afford800 mg (70%) of title compound as a yellow oil. LCMS: [M+H]⁺ 262.05.

Int-A11:3-(2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)propanoicacid

Step 1: Tert-butyl3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]ethoxy)propanoate

A solution of Int-A6 (1.1 g, 3.4 mmol, 1 equiv), Cs₂CO₃ (2.2 g, 6.8mmol, 2 equiv), tert-butyl 3-(2-hydroxyethoxy)propanoate (649.2 mg, 3.41mmol, 1 equiv) in MeCN (20 mL) was stirred for 18 h at RT. The resultingmixture was concentrated under reduced pressure. The residue was appliedonto a silica gel column eluting with EtOAc/petroleum ether (16/84) toafford 1 g (61%) of title compound as a yellow oil. LCMS: [M+H]⁺ 483.21.

Step 2:3-(2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)propanoicAcid

A solution of tert-butyl3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]ethoxy)propanoate(450 mg, 0.93 mmol, 1 equiv) and TFA (1 mL) in DCM (10 mL) was stirredfor 3 h at RT. The resulting mixture was concentrated under reducedpressure and the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford 110 mg (40%) of titlecompound as a white oil. LCMS: [M+H]⁺ 297.06.

Int-A12:3-(2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)propanoicAcid

Step 1: Methyl 3-(2-aminoethoxy)propanoate

A solution of methyl3-(2-[[(tert-butoxy)carbonyl]amino]ethoxy)propanoate (800 mg, 3.24 mmol,1 equiv) in HCl/dioxane (10 mL) was stirred for 30 min at RT. Theresulting mixture was concentrated under reduced pressure to afford 476mg of title compound as a yellow crude oil. LCMS: [M+H]⁺ 148.09.

Step 2: Methyl3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)propanoate

A solution of methyl 3-(2-aminoethoxy)propanoate (476 mg, 3.23 mmol, 1equiv), TEA (981.8 mg, 9.70 mmol, 3 equiv), and Int-A6 (1.06 g, 3.23mmol, 1 equiv) in EtOH (10 mL) was stirred for 60 min at RT. Theresulting mixture was concentrated under vacuum. The residue waspurified by silica gel column chromatography eluting withEtOAc/petroleum ether (28/72, v/v) to afford 259 mg (18%) of titlecompound as a yellow oil. LCMS: [M+H]⁺ 440.18.

Step 3: Methyl3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)propanoate

A solution of methyl3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)propanoate(259 mg, 0.59 mmol, 1 equiv) in HCl/dioxane (10 mL/4M) was stirred for16 h at RT. The resulting mixture was concentrated under reducedpressure to afford 182 mg of title compound as a yellow oil. LCMS:[M+H]⁺ 310.09.

Step 4:3-(2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)propanoicacid

A solution of methyl3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)propanoate(182 mg, 0.59 mmol, 1 equiv) and LiOH.H₂O (123.5 mg, 2.94 mmol, 5 equiv)in MeOH (5 mL) and H₂O (1 mL) was stirred for 3 h at RT. The pH value ofthe solution was adjusted to 7 with aqueous HCl. The resulting solutionwas extracted with 3×3 mL of DCM and the aqueous layers combined andconcentrated under vacuum. After concentration, the residue was purifiedby C18 reverse phase chromatography eluting with H₂O/ACN to afford 100mg (58%) of title compound as a white solid. LCMS: [M+H]⁺ 296.08.

Int-A13:3-[(2S)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoicAcid

Step 1:5-[[(2S)-1-Hydroxypropan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of Int-A6 (8 g, 24 mmol, 1 equiv), TEA (2.463 g, 24 mmol, 1equiv), and (2S)-2-aminopropan-1-ol (1.829 g, 24 mmol, 1 equiv) in EtOH(60 mL) was stirred for 1 h at 60° C. The solvent was concentrated undervacuum and the residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1/1) to afford 5.39 g (58%) of title compound asa yellow oil. LCMS [M+H]⁺ 367.44.

Step 2:3-[(2S)-2-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate

A solution of5-[[(2S)-1-hydroxypropan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(5.39 g, 15 mmol, 1 equiv), methyl prop-2-enoate (13.24 g, 147 mmol, 10equiv), and Cs₂CO₃ (4.773 g, 15 mmol, 1 equiv) in MeCN (50 mL) wasstirred for 4 h at 25° C. The solvent was concentrated under vacuum, theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1/1) to afford 3.12 g (42%) of title compound asa white solid. LCMS [M+H]⁺ 454.53.

Step 3:3-[(2S)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate

A solution of methyl3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate(3.12 g, 1 equiv) and TFA (10 mL) in DCM (40 mL) was stirred 0.5 h at25° C. The resulting mixture was concentrated under vacuum to afford 2.1g (93%) of title compound as a white solid.

Step 4:3-[(2S)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoicAcid

A solution of methyl3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate(2.12 g, 7 mmol, 1 equiv), LiOH.H₂O (1.378 g, 33 mmol, 5 equiv) in MeOH(15 mL) and H₂O (15 mL) was stirred for 0.5 h at 25° C. The pH value ofthe solution was adjusted to 6 with TFA. The resulting mixture wasconcentrated under vacuum and the residue was purified by C18 reversephase chromatography eluting with H₂O/CH₃CN (6:1) to afford 2.1 g (90%)of title compound as a yellow oil. LCMS [M+H]⁺ 310.25.

Int-A14:3-[2-[(5-Bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoic Acid

Step 1: Tert-butyl3-[2-[(5-bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate

A solution of Int-A8 (4 g, 10.4 mmol, 1.0 equiv), tert-butyl3-(2-hydroxyethoxy)propanoate (1.99 g, 10.4 mmol, 1.0 equiv) and Cs₂CO₃(6.82 g, 20.9 mmol, 2 equiv) in MeCN (30 mL) was stirred for 2 h at 60°C., and then the solid was filtered and the resulting solution wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography eluting with EtOAc/petroleum ether to afford2.2 g (43%) of title compound as a light yellow oil. LCMS [M+H]⁺ 493.13,495.13

Step 2:3-[2-[(5-Bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoic Acid

A solution of tert-butyl3-[2-[(5-bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate(1.66 g, 1 equiv) and TFA (2 mL) in DCM (10 mL) was stirred for 2 h atRT, and then the resulting solution was concentrated under reducedpressure to afford 380 mg (37%) of title compound as a yellow oil. LCMS[M+H]⁺ 307.10.

Int-A15:3-[2-[(5-Methyl-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoicAcid

Step 1: Tert-butyl3-(2-((5-methyl-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)oxy)ethoxy)propanoate

A solution of tert-butyl3-[2-[(5-bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate(2 g, 4.05 mmol, 1 equiv), methylboronic acid (485.2 mg, 8.11 mmol, 2equiv), Pd(dppf)Cl₂ (296.6 mg, 0.41 mmol, 0.1 equiv), and CsF (1847.0mg, 12.16 mmol, 3 equiv) in dioxane (15 mL) and H₂O (3 mL) was stirredfor 2 h at 80° C. The solvent was concentrated under vacuum and theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether to afford 1.5 g (86%) of title compound as ayellow oil. LCMS [M+H]⁺ 429.23.

Step 2:3-[2-[(5-Methyl-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoicAcid

A solution of tert-butyl3-[2-[(5-methyl-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate(1.5 g, 1 equiv) in HCl/dioxane (30 mL/4M) was stirred overnight at 25°C. The resulting mixture was concentrated under reduced pressure toafford 800 mg (94%) of title compound as a yellow crude oil. LCMS [M+H]⁺243.09.

Int-A16:3-[2-[(5-Cyano-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoic Acid

Step 1:3-[2-[(5-Bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate

A solution of Int-A8 (4 g, 10.41 mmol, 1 equiv), Cs₂CO₃ (10.14 g, 31.12mmol, 2.99 equiv), and tert-butyl 3-(2-hydroxyethoxy)propanoate (3.97 g,20.87 mmol, 2.00 equiv) in DMF (40 mL) was stirred for 18 h at RT. Thereaction was then quenched by the addition of 40 mL of water. Theresulting solution was extracted with 3×50 mL of EtOAc and the organiclayers combined and dried over anhydrous sodium sulfate. The organiclayers were concentrated under vacuum and the residue was applied onto asilica gel column eluting with EtOAc/petroleum ether (1/9) to afford 2.2g (43%) of title compound as a yellow oil. LCMS [M+H]⁺ 493.13, 495.13. 2g of4-bromo-5-(2-hydroxyethoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one was isolated as a by-product of the reaction duringpurification and was used as a starting material for the synthesis ofInt-A19, Step 1. LCMS [M+H]⁺: 365.05, 367.05.

Step 2: Tert-butyl3-[2-[(5-cyano-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate

A solution of tert-butyl3-[2-[(5-bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate(2.2 g, 4.46 mmol, 1 equiv), and CuCN (800 mg, 8.93 mmol, 2.00 equiv) inNMP (20 mL) was stirred for 23 h at 120° C. The reaction was thenquenched by the addition of 20 mL of water and the resulting solutionwas extracted with 3×30 mL of EtOAc and the organic layers were combinedand dried over anhydrous calcium chloride. The organic layers wereconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography with EtOAc/petroleum ether (3/7) toafford 800 mg (41%) of title compound as a yellow oil. LCMS [M+H]⁺254.07.

Step 3:3-[2-[(5-Cyano-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoic Acid

A solution of tert-butyl3-[2-[(5-cyano-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate(800 mg, 1.82 mmol, 1 equiv) in HCl/dioxane (10 mL/4M) was stirred 18 hat RT. The resulting mixture was concentrated under reduced pressure toafford 350 mg (76%) of title compound as a yellow crude oil. LCMS [M+H]⁺254.07.

Int-A17:2-[5-(Hydroxymethyl)oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethan-1-one

Step 1: 1-(Benzyloxy)hex-5-en-2-ol

To a solution of bromo(prop-2-en-1-yl)magnesium (27.4 mL, 1.50 equiv) inTHF (20 mL) was added dropwise 2-[(benzyloxy)methyl]oxirane (3 g, 18.27mmol, 1.00 equiv) under nitrogen at −40° C. The resulting solution wasstirred for 1 h at −40° C. and the resulting solution was quenched by100 mL with aqueous NH₄Cl, and extracted with 3×100 mL of EtOAc. Theorganic layers were combined, washed with 1×100 mL of brine, dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(1:5) to afford 2.16 g (57%) of title compound as a yellow oil. LCMS[M+H]⁺ 207.13.

Step 2: Methyl (2Z)-7-(benzyloxy)-6-hydroxyhept-2-enoate

Under nitrogen, a solution of 1-(benzyloxy)hex-5-en-2-ol (2 g, 9.70mmol, 1.00 equiv), methyl prop-2-enoate (4.17 g, 48.44 mmol, 5.00 equiv)and Grubbs 2nd generation catalyst (82 mg, 0.01 equiv) in DCM (25 mL)was stirred for 4 h at 40° C. The resulting solution was concentratedunder vacuum and the residue was purified by C18 reverse phasechromatography eluting with H₂O/ACN to afford 1.4 g (55%) of titlecompound as yellow oil. LCMS [M+H]⁺ 265.14.

Step 3: Methyl 2-[5-[(benzyloxy)methyl]oxolan-2-yl]acetate

A solution of methyl (2Z)-7-(benzyloxy)-6-hydroxyhept-2-enoate (46 g, 1equiv) and NaH (0.7 g, 0.1 equiv) in THF (200 mL) was stirred for 12 hat 25° C. The resulting solution was then quenched with 200 mL of water,extracted with 3×200 mL of DCM, and the organic layers combined andwashed with 1×100 mL of brine, dried over anhydrous sodium sulfate andconcentrated under vacuum to afford 46 g of title compound as brown oil.LCMS [M+H]⁺ 265.14.

Step 4: 2-[5-[(Benzyloxy)methyl]oxolan-2-yl]acetic Acid

A solution of methyl 2-[5-[(benzyloxy)methyl]oxolan-2-yl]acetate (46 g,174.03 mmol, 1 equiv) and LiOH.H₂O (14.6 g, 350 mmol, 2 equiv) in THF(200 mL) and H₂O (200 mL) was stirred for 2 h at 25° C. The resultingsolution was washed with 1×200 ml of DCM, the aqueous layers wascombined and the pH value of the aqueous layer was adjusted to 4 withHCl (1M). After concentration, the residue were dissolved in 100 mL ofEtOH and the solids were filtered out. The resulting solution wasconcentrated under vacuum to afford 40 g (92%) of title compound as alight yellow oil. LCMS [M+H]⁺ 251.12.

Step 5:2-[5-[(Benzyloxy)methyl]oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethan-1-one

A solution of 2-[5-[(benzyloxy)methyl]oxolan-2-yl]acetic acid (3 g,11.99 mmol, 1 equiv), 1-[5-(trifluoromethyl)pyridin-2-yl]piperazine (1.7g, 7.35 mmol, 0.61 equiv), HATU (4.6 g, 11.99 mmol, 1 equiv), and DIPEA(4.6 g, 35.96 mmol, 3 equiv) in DMF (50 mL) was stirred for 4 h at RT.The reaction was then quenched by the addition of 100 mL of water. Theresulting solution was extracted with 3×60 mL of EtOAc and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography eluting with EtOAc/petroleum ether (3/2) to afford 3.2 g(58%) of title compound as a yellow oil. LCMS [M+H]⁺ 464.15.

Step 6:2-[5-(Hydroxymethyl)oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethan-1-one

Under H₂ (g) atmosphere, a solution2-[5-[(benzyloxy)methyl]oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethan-1-one(3.2 g, 6.90 mmol, 1 equiv), palladium 10% on carbon (1 g, 9.40 mmol,1.36 equiv) in MeOH (50 mL) was stirred overnight at 50° C. The solidswere filtered and the resulting mixture was concentrated under reducedpressure to afford 1.7 g (66%) of title compound as a colorless oil.LCMS [M+H]⁺ 374.10.

Int-A18: 1-[5-(Trifluoromethyl)pyridin-2-yl]piperazine

This compound was purchased from commercial sources: CAS [132834-58-3].

Int-A19:6-[4-(3-[2-[(5-Bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1:6-[4-(3-[2-[(5-Bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of4-bromo-5-(2-hydroxyethoxy)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1.0 g, 2.74 mmol, 1 equiv), Cs₂CO₃ (2.652 g, 8.14 mmol, 2.97 equiv),and Int-A25 (0.99 g, 4.09 mmol, 1.49 equiv) in DMF (20 mL) was stirredfor 24 h at RT. The reaction was then quenched by the addition of 20 mLof water and the resulting solution was extracted with 3×30 mL of EtOAcand the organic layers were combined and dried over anhydrous sodiumsulfate. The organic layers were concentrated under reduced pressure andthe residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (9/1) to afford 350 mg (21%) of title compound asa yellow oil. LCMS [M+H]⁺ 609.16.

Int-A20:5-Chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

Step 1:4,5-Dibromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydropyridazin-3-one

To a solution of 4,5-dibromo-2,3-dihydropyridazin-3-one (250 g, 984.71mmol, 1 equiv) in DMF (2.5 L) was added NaH (59.1 g, 1477.07 mmol, 1.50equiv, 60%) in several batches at 0-10° C. followed by the addition of1-(chloromethyl)-4-methoxybenzene (230.3 g, 1470.53 mmol, 1.49 equiv) at0° C. The resulting solution was stirred for 3 h at RT. The reaction wasthen quenched by the addition of 5 L of water/ice and extracted with2×2.5 L of DCM. The organic layers were combined and concentrated. Thesolids were washed by MeOH (500 mL×2) to afford 290 g (79%) of titlecompound as a solid. LCMS [M+H]⁺ 378.00.

Step 2:5-Methoxy-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of4,5-dibromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydropyridazin-3-one (290g, 775.33 mmol, 1 equiv), potassium hydroxide (130.5 g, 2326.00 mmol,3.00 equiv) in MeOH (2.5 L) was stirred for 2 h at RT. The resultingmixture was concentrated to 500 mL and the solids were collected byfiltration. The resulting cake was slurried for 1 h in water (1 L) toafford 232 g (92%) of title compound as a solid. LCMS [M+H]⁺ 326.90.

Step 3:5-Methoxy-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of4-bromo-5-methoxy-2-[(4-methoxyphenyl)methyl]-2,3-dihydropyridazin-3-one(232 g, 713.49 mmol, 1 equiv), methyl 2,2-difluoro-2-sulfoacetate (411.2g, 2140.44 mmol, 3.00 equiv), and CuI (67.9 g, 356.52 mmol, 0.50 equiv)in NMP (1.2 L) was stirred for 3 h at 100° C. The reaction was thenquenched by the addition of 1.5 L of water. The resulting solution wasextracted with 3×1 L of DCM. The organic layers were combined andconcentrated. The residue was applied onto a silica gel column withEtOAc/petroleum ether (1/1). The collected fractions were combined andconcentrated to afford the crude oil to which was added 1 L of water.The solids were collected by filtration and washed with 100 mL of MeOHto afford 170 g (76%) of title compound as a solid. LCMS [M+H]⁺ 315.10.

Step 4:5-Hydroxy-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

To a solution of5-methoxy-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(170 g, 540.95 mmol, 1 equiv) in DMF (850 mL) was added TMSI (140 g,699.67 mmol, 1.29 equiv) dropwise at 20° C. The resulting solution wasstirred for 20 h at 85° C. The reaction mixture was then quenched by theaddition of 850 mL of water and the resulting solution was extractedwith 3×850 mL of DCM and the organic layers combined and dried overanhydrous sodium sulfate. The organic layers were concentrated undervacuum and the crude product was purified by silica gel columnchromatography and then recrystallized with MtBE to afford 120 g (74%)of title compound as a white solid. LCMS [M+H]⁺ 301.07.

Step 5:5-Chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

To a solution of5-hydroxy-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(110 g, 366.38 mmol, 1 equiv) in DMF (550 mL) was added oxalicdichloride (93 g, 732.75 mmol, 2.00 equiv) dropwise at 0-5° C. Theresulting solution was stirred for 8 h at RT. The reaction was thenquenched by the addition of 550 mL of water. The solids were collectedby filtration to afford 108 g (93%) of title compound as a white solid.LCMS [M+H]⁺ 319.04 [M+H]⁺, ¹H NMR (30 MHz, DMSO-d₆) δ 8.22 (d, J=0.8 Hz,1H), 7.33-7.22 (m, 2H), 6.94-6.84 (m, 2H), 5.18 (s, 2H), 3.71 (s, 3H).

Int-A21:1-[4-[5-(Trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]prop-2-en-1-one

A solution of Int-A2 (2.2 g, 7 mmol, 1 equiv), TEA (2.924 g, 29 mmol, 4equiv), and prop-2-enoyl chloride (1.954 g, 11 mmol, 10.00 equiv) inMeOH (20 mL) was stirred for 4.5 h at 0° C. The solids were filtered outand washed by 30 mL x 2 of EtOAc. The organic layers were then combined,concentrated, and then applied onto a silica gel column withchloroform/methanol (11/1) to afford 1.83 g (58%) of the title compoundas a yellow solid. LCMS [M+H]⁺ 287.25.

Int-A22: 1-[4-(5-Chloropyridin-2-yl)piperazin-1-yl]prop-2-en-1-one

A solution of Int-A5 (2.4 g, 8.92 mmol, 1.00 equiv), TEA (4 g, 39.5mmol, 4.00 equiv), and prop-2-enoyl prop-2-enoate (3.64 g, 28.9 mmol,3.00 equiv) in DCM (20 mL) was stirred for 1.5 h at RT. The solvent wasconcentrated under vacuum and the residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (1:1) to afford 1280 mg (57%)of title compound as a yellow oil. LCMS [M+H]+ 252.09.

Int-A23: 1-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]prop-2-en-1-one

A solution of Int-A3 (1 g, 3.70 mmol, 1.00 equiv), TEA (1.5 g, 14.82mmol, 4.00 equiv), and prop-2-enoyl prop-2-enoate (700 mg, 5.55 mmol,1.50 equiv) in DCM (20 mL) was stirred for 1 h at RT. The solvent wasconcentrated under vacuum and the residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (2:3) to afford 720 mg (77%)of title compound as a white solid. LCMS [M+H]+ 253.07.

Int-A24: 2-[4-(Prop-2-enoyl)piperazin-1-yl]pyrimidine-5-carbonitrile

A solution of Int-A1 (6.4 g, 33.82 mmol, 1 equiv), prop-2-enoylprop-2-enoate (5.1 g, 40.44 mmol, 1.20 equiv) and TEA (6.8 g, 67.20mmol, 1.99 equiv) in DCM (40 mL) was stirred for 1 h at roomtemperature, then the resulting solution was concentrated under vacuum,and the residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (7:3) to afford 3.6 g (43.75%) of the titlecompound as a white solid. LCMS [M+H]+: 244.12.

Int-A25: 6-[4-(Prop-2-enoyl)piperazin-1-yl]pyridine-3-carbonitrile

Prop-2-enoyl prop-2-enoate (17.42 g, 138.132 mmol, 1.30 equiv) was addedto a solution of Int-A4 (20 g, 106.251 mmol, 1 equiv), and TEA (32.25 g,318.752 mmol, 3 equiv) in DCM (500 mL) at −40° C. The resulting solutionwas stirred for another 1 h at −40° C. The reaction was quenched by 500mL of water and extracted with 2×500 mL of DCM. After concentration, theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (70:30) to afford 16.4 g (64%) of title compoundas a yellow solid. LCMS [M+H]+ 243.13.

Int-A26:5-(Trifluoromethyl)-2-(4-(vinylsulfonyl)piperazin-1-yl)pyrimidine

A solution of Int-A2, 2-chloroethane-1-sulfonyl chloride, and TEA (305.0mg, 3.02 mmol, 3.50 equiv) in DCM (6 mL) was stirred for 2 h at RT. Theresulting mixture was concentrated under reduced pressure and theresidue was eluted onto a silica gel column with EtOAc/petroleum ether(1:5) to afford 210 mg (75.7%) of title compound as a white solid. LCMS[M+H]+ 323.07.

Int-A27: 1-[5-(Trifluoromethyl)-1,3-thiazol-2-yl]piperazineHydrochloride

Step 1: Tert-butyl 4-(5-(trifluoromethyl)thiazol-2-yl)piperazine-1-carboxylate

A solution of 2-bromo-5-(trifluoromethyl)thiazole (3.00 g, 12.9 mmol,1.00 equiv), tert-butyl piperazine-1-carboxylate (2.41 g, 12.9 mmol,1.00 equiv), and Cs₂CO₃ (8.43 g, 25.9 mmol, 2.00 equiv) in NMP (20.0 mL)was stirred for 1 h at 110° C. The reaction was then quenched by theaddition of 50 mL of water and extracted with 3×50 mL of EtOAc. Afterconcentration under reduced pressure, the residue was purified by silicagel column chromatography with EtOAc/petroleum ether (15/85) to afford2.56 g (95%) of title compound as a yellow solid. LCMS [M+H]+ 338.11.

Step 2: 1-[5-(Trifluoromethyl)-1,3-thiazol-2-yl]piperazine Hydrochloride

A solution of tert-butyl4-(5-(trifluoromethyl)thiazol-2-yl)piperazine-1-carboxylate (2.50 g,7.41 mmol, 1.00 equiv) and HCl (gas) in 1,4-dioxane (20.0 mL) wasstirred for 30 min at RT. The resulting mixture was concentrated undervacuum to afford 2.26 g (95%) of the title compound as a white solid.LCMS [M+H]+ 274.03.

Int-A28: 5-(Trifluoromethyl)-2-(4-(vinylsulfonyl)piperazin-1-yl)thiazole

A solution of Int-A27 (2.25 g, 9.48 mmol, 1.00 equiv), TEA (4.80 g,0.047 mmol, 5 equiv), and 2-chloroethane-1-sulfonyl chloride (1.86 g,0.011 mmol, 1.20 equiv) in DCM (30.0 mL) was stirred for 1 h at 0° C. ina water/ice bath. The reaction mixture was quenched by the addition ofMeOH followed by concentration under reduced pressure. The residue waspurified by a silica gel column with EtOAc/petroleum ether (18/82) toafford 1.74 g (54.9%) of title compound as a white solid. LCMS [M+H]+328.03.

Int-A29:5-Mercapto-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of Int-A20 (2 g, 6.3 mmol, 1 equiv), NaHS (1.4 g, 25.1 mmol,4 equiv), and TEA (1.9 g, 18.9 mmol, 3 equiv) in EtOH (10 mL) wasstirred for 40 min at 70° C. After concentration under reduced pressure,the residue was purified by C18 reverse phase chromatography elutingwith H₂O/CH₃CN to afford 1.8 g (90.7%) of title compound as a yellowsolid. LCMS [M+H]+ 317.06.

SYNTHESIS OF EXAMPLE COMPOUNDS Example 1:5-[5-[(1-acetylpiperidin-4-yl)oxy]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of 1-bromo-4,5-bis(bromomethyl)-2-fluorobenzene

A solution of 1-bromo-2-fluoro-4,5-dimethylbenzene (5 g, 24.62 mmol, 1equiv), NBS (10.85 g, 60.96 mmol, 2.476 equiv), AIBN (1.98 g, 12.06mmol, 0.490 equiv) in CCl₄ (50 mL) was stirred for 12 h at 80° C. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford 5.4 g (61%) of the titlecompound as a yellow solid. LCMS (ESI, m/z): 360.80 [M+H]⁺.

Step 2: Synthesis of 5-bromo-6-fluoro-2,3-dihydro-1H-isoindole

A solution of 1-bromo-4,5-bis(bromomethyl)-2-fluorobenzene (3 g, 8.31mmol, 1 equiv) in NH₃/MeOH (300 mL, 1M) was stirred for 2 h at 5° C. Theresulting mixture was concentrated under vacuum to afford 2.8 g (crude)of the title compound as a yellow solid. LCMS (ESI, m/z): 215.97 [M+H]⁺.

Step 3: Synthesis of5-(5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of 5-bromo-6-fluoro-2,3-dihydro-1H-isoindole (1.2 g, 5.55mmol, 1 equiv), Int-A6 (2.17 g, 6.60 mmol, 1.188 equiv), TEA (1.7 g,16.80 mmol, 3.025 equiv) in EtOH (40 mL) was stirred for 2 h at 80° C.The resulting mixture was concentrated under vacuum. The residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(15/85) to afford 870 mg (30.81%) of the title compound as a brownsolid. LCMS (ESI, m/z): 510.06 [M+H]⁺.

Step 4: Synthesis of5-(5-fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-(5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(850 mg, 1.67 mmol, 1 equiv), LiOH.H₂O (154.6 mg, 3.68 mmol, 2.203equiv), BHMPO (287 mg, 0.84 mmol, 0.5 equiv), Cu(acac)₂ (220 mg, 0.84mmol, 0.5 equiv) in DMSO (16 mL) and H₂O (4 mL) was stirred for 2 h at80° C. The reaction was then quenched by the addition of 20 mL of water.The resulting solution was extracted with 3×30 ml of EtOAc and theorganic layers combined and dried over anhydrous sodium sulfate. Afterconcentration, the residue was applied onto a silica gel column elutingwith EtOAc/petroleum ether (25/75) to afford 260 mg (35%) of the titlecompound as a yellow solid. LCMS (ESI, m/z): 446.14 [M+H]⁺.

Step 5: Synthesis of Tert-Butyl4-([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate

A solution of5-(5-fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(260 mg, 0.58 mmol, 1 equiv), tert-butyl 4-iodopiperidine-1-carboxylate(362.6 mg, 1.17 mmol, 1.997 equiv), K₂CO₃ (126 mg, 0.91 mmol, 1.562equiv) in DMF (20 mL) was stirred for 12 h at 80° C. The reaction wasthen quenched by the addition of 20 mL of water. The resulting solutionwas extracted with 3×30 ml of EtOAc and the organic layers combined anddried over anhydrous sodium sulfate. After concentration, the residuewas applied onto a silica gel column eluting with EtOAc/petroleum ether(20/80) to afford 500 mg (crude) of the title compound as brown oil.LCMS (ESI, m/z): 629.25 [M+H]⁺.

Step 6: Synthesis of5-[5-fluoro-6-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of tert-butyl4-([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate(500 mg, 0.80 mmol, 1 equiv) in HCl/dioxane (5 mL) was stirred for 12 hat room temperature. After concentration, the residue was purified byC18 reverse phase chromatography eluting with H₂O/CH₃CN to afford 330 mg(crude) of the title compound as a yellow oil. LCMS (ESI, m/z): 399.25[M+H]⁺.

Step 7: Synthesis of5-[5-[(1-acetylpiperidin-4-yl)oxy]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[5-fluoro-6-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(330 mg, 0.83 mmol, 1 equiv), Ac₂O (85.2 mg, 0.83 mmol, 1.007 equiv),TEA (372 mg, 3.68 mmol, 4.438 equiv) in DCM (5 mL) was stirred for 1 hat room temperature. After concentration, the residue was purified byC18 reverse phase chromatography eluting with H₂O/CH₃CN. Then theresidue was further purified by Prep-HPLC yielding the title compound(44 mg, 12%) as a white solid. LCMS (ESI, m/z): 441.39 [M+H]⁺, ¹HNMR(DMSO-d₆, 300 MHz) δ: 12.52 (s, 1H), 7.96 (s, 1H), 7.29 (dd, J=11.8, 9.4Hz, 2H), 4.90 (br, 4H), 4.59 (dt, J=8.0, 4.2 Hz, 1H), 3.83 (dd, J=13.3,6.4 Hz, 1H), 3.73-3.61 (m, 1H), 3.59-3.47 (m, 1H), 3.39-3.13 (m, 1H),2.01-1.81 (m, 5H), 1.88-1.42 (m, 2H).

Example 2:5-[4-[(1-acetylpiperidin-4-yl)oxy]-7-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of 2-benzyl-4-bromo-7-fluoro-2,3-dihydro-1H-isoindole

A solution of 1-bromo-2,3-bis(bromomethyl)-4-fluorobenzene (2.2 g, 6.10mmol, 1 equiv), phenylmethanamine (0.66 g, 6.16 mmol, 1.010 equiv),KHCO₃ (1.5 g, 14.98 mmol, 2.457 equiv) in ACN (200 mL) was stirred for 3h at 75° C. in an oil bath. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (5/95) to afford 660 mg (35%) of the titlecompound as a yellow solid. LCMS (ESI, m/z): 306.02 [M+H]⁺.

Step 2: Synthesis of2-benzyl-4-fluoro-7-methoxy-2,3-dihydro-1H-isoindole

A solution of MeOH (5 mL),2-benzyl-4-bromo-7-fluoro-2,3-dihydro-1H-isoindole (700 mg, 2.29 mmol, 1equiv), Pd₂(allyl)₂Cl₂ (56.0 mg, 0.15 mmol, 0.067 equiv), RockPhos(107.2 mg, 0.23 mmol, 0.100 equiv), Cs₂CO₃ (1492.1 mg, 4.58 mmol, 2.003equiv) in Toluene (12 mL) was stirred for 3 h at 80° C. in an oil bathwith the atmosphere of nitrogen. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column elutingwith EtOAc/petroleum ether (5/95) to afford 500 mg (85%) of the titlecompound as yellow oil. LCMS (ESI, m/z): 258.12 [M+H]⁺.

Step 3: Synthesis of 2-benzyl-7-fluoro-2,3-dihydro-1H-isoindol-4-ol

A solution of 2-benzyl-4-fluoro-7-methoxy-2,3-dihydro-1H-isoindole (500mg, 1.94 mmol, 1 equiv) in DCM (5 mL) was stirred at 0° C. To this wasadded BBr₃ (5 mL, 52.89 mmol, 27.217 equiv) dropwise with stirring at 0°C. The resulting solution was stirred for 12 h at room temperature. Thereaction was then quenched by the addition of 10 mL of methanol. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column eluting with EtOAc/petroleum ether (15/85) toafford 456 mg (96.5%) of the title compound as a white solid. LCMS (ESI,m/z): 244.11 [M+H]⁺.

Step 4: Synthesis of 7-fluoro-2,3-dihydro-1H-isoindol-4-ol Hydrochloride

A solution of 2-benzyl-7-fluoro-2,3-dihydro-1H-isoindol-4-ol (400 mg,1.64 mmol, 1 equiv), Pd/C (40.1 mg), HCl (1M, 3 mL). The resultingsolution was stirred for 1 h at room temperature. The solids werefiltered out. The filtrate was concentrated under vacuum. This resultedin 210 mg (67%) of the title compound as a yellow solid. LCMS (ESI,m/z): 154.06 [M+H]⁺.

Step 5: Synthesis of5-(4-fluoro-7-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of 7-fluoro-2,3-dihydro-1H-isoindol-4-ol hydrochloride (100mg, 0.53 mmol, 1 equiv), Int-A6 (214 mg, 0.65 mmol, 1.234 equiv), TEA(194.7 mg, 1.92 mmol, 3.648 equiv) in EtOH (3 mL) was stirred for 2 h at80° C. in an oil bath. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column eluting withEtOAc/petroleum ether to afford 140 mg (60%) of the title compound asyellow oil. LCMS (ESI, m/z): 446.14 [M+H]⁺.

Step 6: Synthesis of Tert-Butyl4-([7-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)piperidine-1-carboxylate

A solution of5-(4-fluoro-7-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(400 mg, 0.90 mmol, 1 equiv), tert-butyl 4-iodopiperidine-1-carboxylate(558 mg, 1.79 mmol, 1.997 equiv), K₂CO₃ (193.8 mg, 1.40 mmol, 1.562equiv) in DMF (5 mL) was stirred for 4 days at 80° C. The reaction wasthen quenched by the addition of 5 mL of water. The resulting solutionwas extracted with 3×30 ml of EtOAc and the organic layers combined anddried over anhydrous sodium sulfate. The organic layer was concentratedunder vacuum. The residue was applied onto a silica gel column elutingwith EtOAc/petroleum ether (50/50) to afford 130 mg (23%) of the titlecompound as a yellow solid. LCMS (ESI, m/z): 629.27 [M+H]⁺.

Step 7: Synthesis of5-[4-fluoro-7-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of tert-butyl4-([7-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)piperidine-1-carboxylate(130 mg, 0.21 mmol, 1.00 equiv) in hydrogen chloride/dioxane (10 mL) wasstirred for 16 h at room temperature. After concentration, the residuewas purified by C18 reverse phase chromatography eluting with H₂O/CH₃CNto afford 80 mg (96%) of the title compound as a white solid. LCMS (ESI,m/z): 399.14 [M+H]⁺.

Step 8: Synthesis of5-[4-[(1-acetylpiperidin-4-yl)oxy]-7-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of TEA (90 mg, 0.89 mmol, 3.00 equiv),5-[4-fluoro-7-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(80 mg, 0.20 mmol, 1.00 equiv), Ac₂O (20.65 mg, 0.20 mmol, 1.00 equiv)in DCM (5 mL) was stirred for 2 h at room temperature. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN. Then the residue was furtherpurified by Prep-HPLC yielding the title compound (18.5 mg, 21%) as awhite solid. LCMS (ESI, m/z): 441.39 [M+H]⁺, ¹HNMR (DMSO-d₆, 300 MHz) δ12.56 (s, 1H), 8.11 (s, 1H), 7.15-7.07 (m, 2H), 5.02 (s, 2H), 4.92 (s,2H), 4.68 (dt, J=6.6, 3.4 Hz, 1H), 3.74-3.57 (m, 2H), 3.45-3.32 (m, 2H),2.02 (s, 3H), 2.00-1.84 (m, 2H), 1.72-1.51 (m, 2H).

Example 3:5-[4-fluoro-6-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one;Formic Acid

Step 1: Synthesis of methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate

A solution of methyl 4-bromo-6-fluoro-2-methylbenzoate (10 g, 40.48mmol, 1.00 equiv), NBS (7.23 g, 40.62 mmol, 1.10 equiv) and AIBN (3.33g, 20.28 mmol, 0.50 equiv) in CCl₄ (150 mL) was stirred for 12 h at 80°C., and then the resulting solution was concentrated under vacuum andthe crude product was purified by C18 reverse phase chromatographyeluting with H₂O/CH₃CN to afford 10 g (76%) of the title compound asyellow oil. LCMS (ESI, m/z): 324.88 [M+H]⁺.

Step 2: Synthesis of 5-bromo-7-fluoro-2,3-dihydro-1H-isoindol-1-one

A solution of 4-bromo-2-(bromomethyl)-6-fluorobenzoate (10 g, 30.68mmol, 1.00 equiv) in NH₃(gas)/MeOH (40 mL, 7M) was stirred for 40 min at40° C., and then the resulting solution was concentrated under vacuum toafford 9.1 g (crude) of the title compound as an off-white solid. LCMS(ESI, m/z): 230.04 [M+H]⁺.

Step 3: Synthesis of Tert-Butyl5-bromo-7-fluoro-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate

To a solution of 5-bromo-7-fluoro-2,3-dihydro-1H-isoindol-1-one (9.1 g,39.56 mmol, 1.00 equiv) and DMAP (977 mg, 8.00 mmol, 0.20 equiv) in THF(70 mL), was added (Boc)₂O (12.99 g, 59.52 mmol, 1.50 equiv), and theresulting solution was stirred for 2 h at room temperature, and then theresulting solution was concentrated under vacuum, The crude product waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN toafford 5.7 g (44%) of the title compound as a white solid. LCMS (ESI,m/z): 330.15 [M+H]⁺.

Step 4: Synthesis of 6-bromo-4-fluoro-2,3-dihydro-1H-isoindole

Under nitrogen, to a solution of tert-butyl5-bromo-7-fluoro-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate (5.7 g,17.26 mmol, 1.00 equiv) and NaBH4 (7.9 g, 208.83 mmol, 12.00 equiv) inTHF (60 mL), BF3/Et2O (36.9 g, 15.00 equiv, 1M) added dropwise, and thenthe resulting solution was stirred for 3 h at 70° C. The resultingsolution was quenched by the addition of 200 mL of water, extracted with3×200 mL of EtOAc and the organic layers combined, washed with 1×200 mLof brine, dried over anhydrous sodium sulfate and concentrated undervacuum, and then the residue was applied onto a silica gel columneluting with DCM/methanol (2:3) to give 2.05 g (55%) of the titlecompound ndole as an off-white solid. LCMS (ESI, m/z): 216.05 [M+H]⁺.

Step 5: Synthesis of5-(6-bromo-4-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of 6-bromo-4-fluoro-2,3-dihydro-1H-isoindole (2.05 g, 9.49mmol, 1.00 equiv),5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(3.12 g, 9.49 mmol, 1.00 equiv) and TEA (2.88 g, 28.46 mmol, 3.00 equiv)in ethanol (20 mL) was stirred for 2 h at 60° C., and then the resultingsolution was concentrated under vacuum, and then the residue was appliedonto a silica gel column eluting with EtOAc/petroleum ether (1:5) toafford 2.1 g (44%) of the title compound as a light brown solid. LCMS(ESI, m/z): 508.39 [M+H]⁺.

Step 6: Synthesis of5-(4-fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-(6-bromo-4-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(2 g, 3.93 mmol, 1.00 equiv), BHMPO (135 mg, 0.41 mmol, 0.10 equiv),Cu(acac)₂ (103 mg, 0.39 mmol, 0.10 equiv) and LiOH.H2O (363 mg, 8.64mmol, 2.20 equiv), DMSO (20 mL) and water (5 mL) was stirred for 12 h at80° C., and then the solids were filtered out, and the resultingsolution was diluted with 100 mL of H₂O, extracted with 3×100 mL ofEtOAc and the organic layers combined, washed with 1×100 mL of brine andconcentrated under vacuum, and then the residue was applied onto asilica gel column eluting with EtOAc/petroleum ether (3:1) to afford 680mg (39%) of the title compound as a green solid. LCMS (ESI, m/z): 446.14[M+H]⁺.

Step 7: Synthesis of Tert-Butyl4-([7-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate

A solution of5-(4-fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(300 mg, 0.67 mmol, 1.00 equiv), tert-butyl4-iodopiperidine-1-carboxylate (629 mg, 2.02 mmol, 3.00 equiv) andpotassium carbonate (279 mg, 2.02 mmol, 3.00 equiv) in DMF (5 mL) wasstirred for 12 h at 80° C., and then the resulting solution was dilutedwith 50 mL of H₂O, extracted with 3×50 mL of EtOAc and the organiclayers combined, washed with 1×50 mL of brine, dried over anhydroussodium sulfate and concentrated under vacuum, and then the residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(3:1) to give 153 mg (36%) of the title compound as yellow oil. LCMS(ESI, m/z): 629.27 [M+H]⁺.

Step 8: Synthesis of5-[4-fluoro-6-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one;Formic Acid

A solution of tert-butyl4-([7-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate(135 mg, 0.21 mmol, 1.00 equiv) in HCl(gas)/dioxane (6 mL, 4M) wasstirred for 2 h at room temperature, and then the resulting solution wasconcentrated under vacuum, and then the crude product was furtherpurified by Pre-HPLC yielding the title compound (34.2 mg, 36%) as awhite solid. LCMS (ESI, m/z): 399.05 [M+H]⁺. ¹HNMR (DMSO-d₆, 300 MHz): δ12.54 (s, 1H), 8.32 (s, 1H), 8.02 (s, 1H), 6.91 (s, 1H), 6.87 (d, J=11.4Hz, 1H), 4.96 (d, J=12.2 Hz, 4H), 4.53 (dr, 1H), 3.05 (dr, 2H), 2.79(dr, 2H), 2.01-1.97 (m, 2H), 1.62-1.60 (m, 2H).

Example 4:5-[6-[(1-acetylpiperidin-4-yl)oxy]-4-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[4-fluoro-6-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one;formic acid (110 mg, 0.28 mmol, 1.00 equiv), TEA (90 mg, 0.89 mmol, 3.00equiv) and Ac₂O (150 mg, 1.47 mmol, 5.00 equiv) in DCM (20 mL) wasstirred for 4 h at room temperature, and then the resulting solution wasconcentrated under vacuum, and then the residue was purified byPrep-HPLC yielding the title compound (18.3 mg, 15%) as a white solid.LCMS (ESI, m/z): 441.05 [M+H]⁺. ¹HNMR (DMSO-d₆, 300 MHz): δ 12.56 (s,1H), 8.03 (s, 1H), 6.92 (d, J=2.0 Hz, 1H), 6.86 (dd, J=11.2, 2.0 Hz,1H), 4.96 (d, J=12.2 Hz, 4H), 4.63 (dt, J=8.1, 4.3 Hz, 1H), 3.88-3.84(m, 1H), 3.69-3.64 (m, 1H), 3.32-3.30 (m, 1H), 3.22-3.14 (m, 1H), 2.01(s, 3H), 1.94-1.88 (m, 2H), 1.67-1.56 (m, 1H), 1.53-1.39 (m, 1H).

Example 5:5-[6-[(1-acetylpiperidin-4-yl)oxy]-5-fluoro-1-methyl-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: synthesis of 4-bromo-2-(bromomethyl)-5-fluorobenzoate

A solution of methyl 4-bromo-5-fluoro-2-methylbenzoate (9.5 g, 38.45mmol, 1.00 equiv), AIBN (3.15 g, 19.18 mmol, 0.50 equiv), NBS (10.31 g,57.93 mmol, 1.50 equiv) in CCl₄ (100 mL) was stirred for 1 overnight at80° C. The resulting mixture was concentrated under vacuum. The residuewas applied onto a silica gel column eluting with EtOAc/petroleum ether(1/50) to afford 12.5 g of the title compound as yellow crude oil. LCMS(ESI, m/z): 324.88 [M+H]⁺.

Step 2: Synthesis of 5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-1-one

A solution of methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate (12.5 g,38.35 mmol, 1.00 equiv) in NH₃/MeOH (150 mL, 7M) was stirred for 3 h at40° C. The solids were collected by filtration after the resultingsolution was cooled to room temperature. This resulted in 7.1 g (80%) ofthe title compound as a white solid. LCMS (ESI, m/z): 229.95 [M+H]⁺.

Step 3: Synthesis of Tert-Butyl5-bromo-6-fluoro-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate

A solution 5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-1-one (7.1 g, 30.87mmol, 1.00 equiv), 4-dimethylaminopyridine (759 mg, 6.21 mmol, 0.20equiv), (Boc)₂O (8 g, 36.66 mmol, 1.20 equiv) in THF (100 mL) wasstirred for 2 h at room temperature. The reaction was then quenched bythe addition of 100 mL of water. The resulting solution was extractedwith 2×100 mL of EtOAc and the organic layers combined and concentratedunder vacuum. This resulted in 9.8 g (96%) of the title compound as awhite solid. LCMS (ESI, m/z): 330.01 [M+H]⁺.

Step 4: Synthesis of Tert-Butyl5-bromo-6-fluoro-3-methyl-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate

A solution of tert-butyl5-bromo-6-fluoro-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate (500 mg,1.51 mmol, 1.00 equiv) in THF (5 mL) was stirred at −70° C. This wasfollowed by the addition of NaHMDS in THF (1.8 mL, 1.20 equiv, 1M) withstirring at −70° C. The resulting solution was stirred for 30 min at−70° C. To this was added iodomethane (213.7 mg, 1.51 mmol, 1.00 equiv).The resulting solution was stirred for 2 h at room temperature. Thereaction was then quenched by the addition of 10 mL of water. Theresulting solution was extracted with 3×10 mL of EtOAc and the organiclayers combined and concentrated under vacuum. The residue was appliedonto a silica gel column eluting with EtOAc/petroleum ether (1/15) toafford 210 mg (40%) of the title compound as a brown solid. LCMS (ESI,m/z): 344.02 [M+H]⁺.

Step 5: Synthesis of Tert-Butyl6-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-isoindole-2-carboxylate

A solution of tert-butyl5-bromo-6-fluoro-3-methyl-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate(210 mg, 0.61 mmol, 1.00 equiv), NaBH₄ (220 mg, 5.97 mmol, 10.00 equiv),BH₃.Et₂O (0.86 mL, 12.00 equiv) in THF (5 mL) was stirred for 3 h at 70°C. The reaction was then quenched by the addition of 10 mL of water. Theresulting solution was extracted with 3×10 mL of EtOAc and the organiclayers combined. The resulting mixture was washed with 2×10 mL of brine.The resulting mixture was concentrated under vacuum. This resulted in180 mg (89%) of the title compound as yellow oil. LCMS (ESI, m/z):330.04 [M+H]⁺.

Step 6: Synthesis of 6-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-isoindoleHydrochloride

A solution of tert-butyl6-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-isoindole-2-carboxylate (180mg, 0.55 mmol, 1.00 equiv) in HCl/dioxane (5 mL, 4M) was stirred for 2 hat room temperature. The solids were collected by filtration to afford130 mg (89%) of the title compound as yellow crude oil. LCMS (ESI, m/z):229.99 [M+H]⁺.

Step 7: Synthesis of5-(6-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(161 mg, 0.49 mmol, 1.00 equiv), TEA (100 mg, 0.99 mmol, 2.00 equiv),6-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-isoindole hydrochloride (130mg, 0.49 mmol, 1.00 equiv) in ethanol (5 mL) was stirred for 3 h at 40°C. The resulting mixture was concentrated under vacuum. The residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(1/6) to afford 114 mg (45%) of the title compound as yellow oil. LCMS(ESI, m/z): 522.08 [M+H]⁺.

Step 8: Synthesis of5-(5-fluoro-6-hydroxy-1-methyl-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-(6-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1.5 g, 2.87 mmol, 1.00 equiv), BHMPO (472 mg, 1.43 mmol, 0.50 equiv),Cu(acac)₂ (376 mg, 1.44 mmol, 0.50 equiv), LiOH.H₂O (241 mg, 5.74 mmol,2.00 equiv) in DMSO (20 mL) and water (5 mL) was stirred for 2 hr at 80°C. The reaction was then quenched by the addition of 50 mL of water. Theresulting solution was extracted with 3×20 mL of EtOAc and the organiclayers combined and concentrated under vacuum. The residue was appliedonto a silica gel column eluting with EtOAc/petroleum ether (1/3) toafford 136 mg (10%) of the title compound as a brown solid. LCMS (ESI,m/z): 460.19 [M+H]⁺.

Step 9: Synthesis of Tert-Butyl4-([6-fluoro-3-methyl-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate

A solution of5-(5-fluoro-6-hydroxy-1-methyl-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(136 mg, 0.30 mmol, 1.00 equiv), potassium carbonate (81.6 mg, 0.59mmol, 2.00 equiv), tert-butyl 4-iodopiperidine-1-carboxylate (276 mg,0.89 mmol, 3.00 equiv) in DMF (10 mL) was stirred for 3 days at 80° C.The reaction was then quenched by the addition of 10 mL of water. Theresulting solution was extracted with 3×10 mL of EtOAc and the organiclayers combined and concentrated under vacuum. The residue was appliedonto a silica gel column eluting with EtOAc/petroleum ether (1/4) toafford 190 mg of the title compound as yellow crude oil. LCMS (ESI,m/z): 643.29 [M+H]⁺.

Step 10: Synthesis of5-[5-fluoro-1-methyl-6-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of tert-butyl4-([6-fluoro-3-methyl-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate(180 mg, 0.28 mmol, 1 equiv) in HCl/dioxane (5 mL) was stirred for 12 hrat room temperature. The resulting mixture was concentrated under vacuumto afford 200 mg (crude) of the title compound as yellow oil.

Step 11: Synthesis of5-[6-[(1-acetylpiperidin-4-yl)oxy]-5-fluoro-1-methyl-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[5-fluoro-1-methyl-6-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(120 mg, 0.29 mmol, 1 equiv), acetic anhydride (30 mg, 0.29 mmol, 1.010equiv), TEA (131 mg, 1.29 mmol, 4.449 equiv) in DCM (5 mL) was stirredfor 2 h at room temperature. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN.Then the residue was further purified by Prep-HPLC yielding the titlecompound (9.9 mg, 7.5%) as a white solid. LCMS (ESI, m/z): 455.42[M+H]⁺, ¹HNMR (DMSO-d₆, 300 MHz) δ: 12.60 (s, 1H), 8.12 (s, 1H), 7.30(s, 1H), 7.27 (s, 1H), 5.64 (d, J=6.9 Hz, 1H), 5.05 (d, J=14.8 Hz, 1H),4.80-4.65 (br, 1H), 4.50 (d, J=14.8 Hz, 1H), 3.90-4.75 (m, 1H),3.73-3.56 (m, 1H), 3.40-3.20 (m, 2H), 2.03 (s, 3H), 1.95-1.80 (m, 2H),1.72-1.80 (m, 2H), 1.49-1.43 (m, 3H).

Example 6:5-[2-[(1-methylpiperidin-4-yl)oxy]-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of5-[2-chloro-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of 2-chloro-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl hydrochloride(5 g, 26.31 mmol, 1.00 equiv), TEA (8 g, 79.06 mmol, 3.00 equiv),5-chloro-4-(trifluoromethyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydropyridazin-3-one(14.3 g, 43.49 mmol, 1.00 equiv) in EtOH (30 mL) was stirred for 2 h at80° C. The solvent was concentrated under vacuum and the residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(1/4) to afford 9.3 g (79%) of the title compound as yellow oil. LCMS(ESI, m/z): 447.12 [M+H]⁺.

Step 2: Synthesis of5-[2-hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[2-chloro-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1.2 g, 2.69 mmol, 1.00 equiv), t-BuBrettphos (196 mg, 0.15 equiv),K₃PO₄ (1.711 g, 8.06 mmol, 3.00 equiv), Pd(OAc)₂ (61 mg, 0.27 mmol, 0.10equiv) in dioxane (15 mL) and water (5 mL) under nitrogen atmosphere wasstirred for 2 h at 100° C. The solvent was concentrated under vacuum andthe residue was applied onto a silica gel column eluting withDCM/methanol (9/1) to afford 700 mg (61%) of the title compound as ayellow solid. LCMS (ESI, m/z): 429.15 [M+H]⁺.

Step 3: Synthesis of Tert-Butyl4-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-2-yl]oxy)piperidine-1-carboxylate

A solution of5-[2-hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(500 mg, 1.17 mmol, 1.00 equiv), Ag₂CO₃ (640 mg, 2.00 equiv), tert-butyl4-iodopiperidine-1-carboxylate (1 g, 3.21 mmol, 3.00 equiv) in DMF (15mL) was stirred for 4 h at 80° C. The resulting solution was dilutedwith 15 mL of water and extracted with 3×15 mL of EtOAc, the organiclayers combined. The resulting solution was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column eluting with EtOAc/petroleum ether (1/4) to afford 500mg (73%) of the title compound as yellow oil. LCMS (ESI, m/z): 612.28[M+H]⁺.

Step 4: Synthesis of5-[2-(piperidin-4-yloxy)-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of tert-butyl4-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-2-yl]oxy)piperidine-1-carboxylate(500 mg, 0.82 mmol, 1.00 equiv) in HCl/dioxane (20 mL, 4M) was stirredovernight at 25° C. The resulting solution was concentrated under vacuumto afford 200 mg (64%) of the title compound as yellow crude oil. LCMS(ESI, m/z): 382.14 [M+H]⁺.

Step 5: Synthesis of5-[2-[(1-methylpiperidin-4-yl)oxy]-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-(2-(piperidin-4-yloxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one(200 mg, 0.52 mmol, 1.00 equiv), (HCHO)_(n) (45 mg, 3.00 equiv), aceticacid (60 mg, 1.00 mmol, 2.00 equiv), NaBH₃CN (95 mg, 1.51 mmol, 3.00equiv) in MeOH (5 mL) was stirred for overnight at 25° C. Afterconcentration, the residue was purified by Prep-HPLC yielding the titlecompound (27.8 mg, 13%) as a white solid. LCMS (ESI, m/z): 396.16[M+H]⁺, ¹H NMR (300 MHz, Methanol-d₄) δ: 8.08 (s, 1H), 7.68 (d, J=8.4Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 5.12 (dq, J=8.1, 4.1 Hz, 1H), 5.02 (s,2H), 4.92 (s, 2H), 2.78 (m, 2H), 2.35 (m, 5H), 2.09 (dd, J=11.9, 7.5 Hz,2H), 1.86 (qd, J=11.8, 10.1, 3.5 Hz, 2H).

Example 7:5-[3-(piperidin-4-yloxy)-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of5-[3-bromo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of 3-bromo-5H,6H,7H-pyrrolo[3,4-b]pyridine hydrochloride (1g, 4.25 mmol, 1.00 equiv) in ethanol (5 mL),5-chloro-4-(trifluoromethyl)-2-[2-(trimethylsilyl)ethoxy]methyl-2,3-dihydropyridazin-3-one(1.6 g, 4.87 mmol, 1.15 equiv) and TEA (1.2 mL) was stirred for 1 h at80° C. The resulting mixture was concentrated under vacuum. The residuewas applied onto a silica gel column with EtOAc/petroleum ether (1:2).This resulted in 1.5 g (72%) of the title compound as a solid. LCMS(ESI, m/z): 491.07 [M+H]⁺.

Step 2: Synthesis of5-[3-hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[3-bromo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1 g, 2.04 mmol, 1.00 equiv), Pd(OAc)₂ (92 mg, 0.41 mmol, 0.20 equiv),t-BuBrettphos (200 mg), K₃PO₄ (1.3 g, 6.12 mmol, 3.01 equiv) indioxane/H₂O (12.5 mL) was stirred for 4 h at 80° C. under an inertatmosphere of nitrogen. The resulting solution was extracted with 250 mLof EtOAc. The resulting mixture was washed with 2×50 mL of water and1×50 mL of Brine. The organic layer was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column with DCM/methanol (9:1). This resulted in 680 mg (78%)of the title compound as a solid. LCMS (ESI, m/z): 429.16 [M+H]⁺.

Step 3: Synthesis of Tert-Butyl4-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-3-yl]oxy)piperidine-1-carboxylateas Oil

A solution of5-[3-hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethyl-silyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(190 mg, 0.44 mmol, 1.00 equiv), Ag₂CO₃ (370 mg) and tert-butyl4-iodopiperidine-1-carboxylate (450 mg, 1.45 mmol, 3.26 equiv) in DMF (5mL) was stirred for 2 h at 80° C. The solids were filtered out. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with DCM/methanol (95:5). This resulted in 60mg (22%) of the title compound as oil. LCMS (ESI, m/z): 612.28 [M+H]⁺.

Step 4: Synthesis of5-[3-(piperidin-4-yloxy)-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

To a stirred solution of tert-butyl4-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-3-yl]oxy)piperidine-1-carboxylate(60 mg, 0.10 mmol, 1.00 equiv) in DCM (5 mL), trifluoroacetic acid (2mL) was added. The resulting solution was stirred for 1 h at roomtemperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN. Then the residuewas further purified by Prep-HPLC yielding the title compound (13.1 mg,35%) as an off-white solid. LCMS (ESI, m/z): 382.15 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.17 (d, J=2.7 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J=2.6 Hz,1H), 4.93 (s, 2H), 4.86 (s, 2H), 4.49 (tt, J=8.6, 3.9 Hz, 1H), 3.05-2.95(m, 2H), 2.71-2.60 (m, 2H), 2.00-1.90 (m, 2H), 1.58-1.44 (m, 2H).

Example 8:5-[3-[(1-acetylpiperidin-4-yl)oxy]-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoro-methyl)-2,3-dihydropyridazin-3-one

To a stirred solution of5-[3-(piperidin-4-yloxy)-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(150 mg, 0.39 mmol, 1.00 equiv) in pyridine (5 mL), Ac₂O (0.5 mL) wasadded. The resulting solution was stirred for 2 h at room temperature.After concentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN. Then the residue was furtherpurified by Prep-HPLC yielding the title compound (50.4 mg, 30%) as awhite solid. LCMS (ESI, m/z): 424.05 [M+H]⁺. ¹H NMR (300 MHz,Methanol-d₄) δ 8.22 (d, J=2.6 Hz, 1H), 8.08 (s, 1H), 7.53 (d, J=2.6 Hz,1H), 5.09 (s, 2H), 4.97 (s, 2H), 4.78-4.67 (m, 1H), 3.94-3.73 (m, 2H),3.61-3.44 (m, 2H), 2.14 (s, 3H), 2.11-1.93 (m, 2H), 1.88-1.67 (m, 2H).

Example 9:5-[4-(piperidin-4-yloxy)-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of5-[4-bromo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(2.3 g, 7.00 mmol, 1.00 equiv), 4-bromo-5H,6H,7H-pyrrolo[3,4-b]pyridinehydrobromide (1.95 g, 6.97 mmol, 1.00 equiv), TEA (3.6 g, 35.58 mmol,5.00 equiv) in EtOH (30 mL) was stirred for 2 h at 80° C. The solventwas concentrated under vacuum and the residue was applied onto a silicagel column eluting with EtOAc/petroleum ether (1/4) to afford 1.1 g(32%) of the title compound as a yellow solid. LCMS (ESI, m/z): 491.06[M+H]⁺.

Step 2: Synthesis of5-[4-hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[4-bromo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(400 mg, 0.81 mmol, 1.00 equiv), Pd(OAc)₂ (19 mg, 0.08 mmol, 0.10equiv), K₃PO₄ (520 mg, 2.45 mmol, 3.00 equiv), t-BuBrettphos (60 mg,0.15 equiv) in dioxane (10 mL) and water (3 mL) under nitrogenatmosphere was stirred for 2 h at 100° C. The solvent was concentratedunder vacuum and the residue was applied onto a silica gel columneluting with DCM/methanol (19/1) to afford 215 mg (62%) of the titlecompound as a yellow solid. LCMS (ESI, m/z): 429.15 [M+H]⁺.

Step 3: Synthesis of Tert-Butyl4-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-4-yl]oxy)piperidine-1-carboxylate

A solution of5-[4-hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(250 mg, 0.58 mmol, 1.00 equiv), Ag₂CO₃ (322 mg, 2.00 equiv), tert-butyl4-iodopiperidine-1-carboxylate (545 mg, 1.75 mmol, 3.00 equiv) in DMF(15 mL) was stirred for 4 h at 80° C. The resulting solution was dilutedwith 15 mL of water and extracted with 3×15 mL of EtOAc, the organiclayers combined. The resulting solution was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column eluting with DCM/methanol (19/1) to afford 240 mg(67%) of the title compound as a yellow solid. LCMS (ESI, m/z): 612.28[M+H]⁺.

Step 4: Synthesis of5-[4-(piperidin-4-yloxy)-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of tert-butyl4-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-4-yl]oxy)piperidine-1-carboxylate(240 mg, 0.39 mmol, 1.00 equiv) in dioxane/HCl (15 mL, 4 M) was stirredfor 1 overnight at 25° C. After concentration, the residue was purifiedby Prep-HPLC yielding the title compound (31.5 mg, 21%) as a whitesolid. LCMS (ESI, m/z): 382.14 [M+H]⁺, ¹H NMR (400 MHz, Methanol-d₄) δ:8.36 (d, J=6.0 Hz, 1H), 8.11 (s, 1H), 7.07 (d, J=6.1 Hz, 1H), 5.03 (d,J=11.7 Hz, 4H), 4.78 (dq, J=8.3, 4.1 Hz, 1H), 3.11 (dt, J=12.9, 4.6 Hz,2H), 2.79 (ddd, J=12.7, 9.2, 3.2 Hz, 2H), 2.39-1.85 (m, 2H), 1.75 (dtd,J=13.0, 8.9, 3.8 Hz, 2H).

Example 10:5-[4-[2-(morpholin-4-yl)ethoxy]-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

Step 1: Synthesis of5-[4-[2-(morpholin-4-yl)ethoxy]-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[4-hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(200 mg, 0.47 mmol, 1.00 equiv), Ag₂CO₃ (387 mg, 3.00 equiv), NaI (140mg, 2.00 equiv), 4-(2-chloroethyl)morpholine (280 mg, 1.87 mmol, 4.00equiv) in DMF (15 mL) was stirred for 2 h at 80° C. The resultingsolution was diluted with 15 mL of water and extracted with 3×15 mL ofEtOAc, the organic layers combined. The resulting solution was driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas applied onto a silica gel column eluting with DCM/methanol (9/1) toafford 200 mg (79%) of the title compound as yellow oil. LCMS (ESI,m/z): 542.23 [M+H]⁺.

Step 2: Synthesis of5-[4-[2-(morpholin-4-yl)ethoxy]-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[4-[2-(morpholin-4-yl)ethoxy]-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(80 mg, 0.15 mmol, 1.00 equiv) in dioxane/HCl (15 mL, 4 M) was stirredfor overnight at 25° C. After concentration, the residue was purified byPrep-HPLC yielding the title compound (22.6 mg, 37%) as a white solid.LCMS (ESI, m/z): 412.15 [M+H]+, 1H NMR (300 MHz, Methanol-d4) δ: 8.40(d, J=5.9 Hz, 1H), 8.11 (s, 1H), 7.06 (d, J=6.0 Hz, 1H), 5.04 (d, J=11.1Hz, 4H), 4.38 (t, J=5.5 Hz, 2H), 3.91-3.56 (m, 4H), 2.89 (t, J=5.4 Hz,2H), 2.77-2.51 (m, 4H).

Example 11:5-[6-methoxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of5-[6-chloro-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(6 g, 18.25 mmol, 1.00 equiv), TEA (5.5 g, 54.35 mmol, 3.00 equiv),6-chloro-1H,2H,3H-pyrrolo[3,4-c]pyridine hydrochloride (3.5 g, 18.32mmol, 1.00 equiv) in ethanol (70 mL) was stirred for 3 h at 80° C. Thereaction mixture was concentrated under vacuum and the residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(4/6) to afford 4.9 g (60%) of the title compound as a yellow solid.LCMS (ESI, m/z): 447.12 [M+H]⁺.

Step 2: Synthesis of5-[6-methoxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[6-chloro-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(500 mg, 1.12 mmol, 1.00 equiv), [Pd(ally)Cl]₂ (41 mg, 0.11 mmol, 0.10equiv), Rockphos (53 mg, 0.11 mmol, 0.10 equiv), Cs₂CO₃ (730 mg, 2.24mmol, 2.00 equiv), methanol (76 mg, 2.37 mmol, 2.12 equiv) in toluene(10 mL) was stirred for 3 h under an atmosphere of nitrogen at 80° C.The resulting mixture was concentrated under vacuum. The residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(3/7) to afford 336 mg (68%) of the title compound as yellow oil. LCMS(ESI, m/z): 443.16 [M+H]⁺.

Step 3: Synthesis of5-[6-methoxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[6-methoxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(336 mg, 0.76 mmol, 1.00 equiv) in hydrogen chloride/dioxane (10 mL) wasstirred for 12 h at room temperature. After concentration, the residuewas purified by C18 reverse phase chromatography eluting with H₂O/CH₃CN.Then the residue was further purified by Prep-HPLC yielding the titlecompound (44.3 mg, 19%) as a white solid. LCMS (ESI, m/z): 313.25[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ: 12.56 (s, 1H), 8.19 (d, J=1.1 Hz,1H), 8.00 (s, 1H), 6.88-6.83 (m, 1H), 4.98-4.93 (m, 4H), 3.86 (s, 3H).

Example 12:5-[6-(piperidin-4-yloxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of5-[6-hydroxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[6-chloro-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(2.5 g, 5.59 mmol, 1.00 equiv), Pd(OAc)₂ (125 mg, 0.56 mmol, 0.10equiv), t-Bubrettphos (407 mg, 0.84 mmol, 0.15 equiv), K₃PO₄ (2.4 g,11.31 mmol, 2.00 equiv) in dioxane (40 mL) and water (4 mL) was stirredfor 3 h at 100° C. The reaction mixture was concentrated under vacuum.The residue was applied onto a silica gel column eluting withDCM/methanol (9/1) to afford 890 mg (37%) of the title compound as abrown solid. LCMS (ESI, m/z): 429.15 [M+H].

Step 2: Synthesis of Tert-Butyl4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl]oxy)piperidine-1-carboxylate

A solution of5-[6-hydroxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(870 mg, 2.03 mmol, 1.00 equiv), Ag₂CO₃ (1.13 g, 2.00 equiv), tert-butyl4-iodopiperidine-1-carboxylate (1.27 g, 4.08 mmol, 2.00 equiv) in DMF(25 mL) was stirred for 10 h at 80° C. The resulting solution wasdiluted with 20 mL of water and extracted with 3×100 ml of EtOAc. Theorganic layers combined, washed with 3×100 mL of brine, dried overNa₂SO₄. The resulting mixture was concentrated under vacuum. The residuewas applied onto a silica gel column eluting with EtOAc/petroleum ether(3/7) to afford 1.21 g (97%) of the title compound as yellow oil. LCMS(ESI, m/z): 612.28 [M+H].

Step 3: Synthesis of of5-[6-(piperidin-4-yloxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of 5 tert-butyl4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl]oxy)piperidine-1-carboxylate(1.21 g, 1.98 mmol, 1.00 equiv) in hydrogen chloride/dioxane (20 mL) wasstirred for 2.5 h at room temperature. After concentration, the residuewas purified by C18 reverse phase chromatography eluting with H₂O/CH₃CN.Then the residue was further purified by Prep-HPLC yielding the titlecompound (17.3 mg, 2%) as a white solid. LCMS (ESI, m/z): 382.35 [M+H]⁺,¹H NMR (400 MHz, Methanol-d4) δ: 8.17-8.11 (m, 1H), 8.07 (s, 1H), 6.81(d, J=1.1 Hz, 1H), 5.14 (dt, J=8.6, 4.5 Hz, 1H), 5.02 (m, 4H), 3.16-3.07(m, 2H), 2.79 (ddd, J=12.7, 9.4, 3.2 Hz, 2H), 2.13-2.01 (m, 2H), 1.72(dtd, J=13.0, 9.0, 3.8 Hz, 2H).

Example 13:5-[6-(piperidin-4-yloxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[6-(piperidin-4-yloxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(290 mg, 0.76 mmol, 1.00 equiv), TEA (154 mg, 1.52 mmol, 2.00 equiv),Ac₂O (93 mg, 0.91 mmol, 1.20 equiv) in DCM (10 mL) was stirred for 2 hat room temperature. After concentration, the residue was purified byC18 reverse phase chromatography eluting with H₂O/CH₃CN. Then theresidue was further purified by Prep-HPLC yielding the title compound(100.1 mg, 31%) as white solid. LCMS (ESI, m/z): 424.39[M+H]⁺, ¹H NMR(300 MHz, Methanol-d₄) δ: 8.18-8.11 (m, 1H), 8.06 (s, 1H), 6.82 (d,J=1.0 Hz, 1H), 5.28 (dq, J=7.5, 3.7 Hz, 1H), 4.89 (m, 4H), 3.98-3.83 (m,1H), 3.79 (ddd, J=11.5, 7.3, 3.8 Hz, 1H), 3.48 (dd, J=15.3, 6.4 Hz, 2H),2.13 (s, 3H), 2.11-1.94 (m, 2H), 1.89-1.65 (m, 2H).

Example 14:5-[5-[2-(dimethylamino)ethoxy]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one;formic acid

Step 1: Synthesis of5-(5-fluoro-6-hydroxyisoindolin-2-yl)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one

A solution of5-(5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(508 mg, 1.00 mmol, 1.00 equiv), Cu(acac)₂ (27 mg, 0.10 equiv), BHMPO(35 mg, 0.10 equiv), LiOH.H₂O (89 mg, 3.72 mmol, 2.10 equiv), water (1mL) in DMSO (4 mL) was stirred for 3 h at 80° C. The solution wasquenched with 20 ml water, then extracted with EtOAc (3×30 mL) and theorganic layers combined. After concentrated under vacuum the residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(7:3) to afford 180 mg (40%) of the title compound as brown oil. LCMS(ESI, m/z): 446.15 [M+H]⁺.

Step 2: Synthesis of5-[5-[2-(dimethylamino)ethoxy]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-(5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(254 mg, 0.50 mmol, 1.00 equiv), 2-(dimethylamino)ethan-1-ol (222.5 mg,2.50 mmol, 5.00 equiv), [Pd(allyl)Cl]₂ (18.3 mg, 0.05 mmol, 0.10 equiv),Rockphos (23.4 mg, 0.05 mmol, 0.10 equiv), Cs₂CO₃ (326 mg, 1.00 mmol,2.00 equiv) in Toluene (20 mL) was stirred for 3 h at 80° C. Theresulting mixture was concentrated, the residue was applied onto asilica gel column eluting with EtOAc/petroleum ether (5/95) to afford 97mg (38%) of the title compound as a brown oil. LCMS (ESI, m/z): 517.00[M+H]⁺.

Step 3: Synthesis of5-[5-[2-(dimethylamino)ethoxy]-6-fluoro-2,3-dihydro-NH-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one;Formic Acid

A solution of5-[5-[2-(dimethylamino)ethoxy]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(88 mg, 0.17 mmol, 1.00 equiv) in HCl/dioxane (15 mL) was stirred for 2h at room temperature. After concentration, the residue was purified byC18 reverse phase chromatography eluting with H₂O/CH₃CN. Then theresidue was further purified by Prep-HPLC yielding the title compound(19.5 mg, 26%) as a white solid. LCMS (ESI, m/z): 387.10 [M+H]⁺, ¹HNMR(300 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.05 (s, 1H), 7.24-7.21 (m, 2H),5.04-5.01 (m, 4H), 4.39 (t, J=5.1 Hz, 2H), 3.52-3.40 (m, 2H), 2.87 (s,6H).

Example 15:5-[4-(pyridin-3-ylmethoxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of 2-bromo-3,4-bis(bromomethyl)pyridine

A solution of 2-bromo-3,4-dimethylpyridine (5 g, 26.87 mmol, 1.00equiv), NBS (10 g, 56.19 mmol, 2.00 equiv) and AIBN (2.22 g, 13.52 mmol,0.50 equiv) in CCl₄ (40 mL) was stirred for 2 h at 80° C., and then theresulting solution was concentrated under vacuum, and then the residuewas applied onto a silica gel column eluting with EtOAc/petroleum ether(2:98) to afford 5.7 g (62%) of the title compound as red oil. LCMS(ESI, m/z): 341.81 [M+H]+.

Step 2: Synthesis of4-bromo-2-[(4-methylbenzene)sulfonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine

A solution of 2-bromo-3,4-bis(bromomethyl)pyridine (2.7 g, 7.85 mmol,1.00 equiv) and sodium hydride (380 mg, 15.83 mmol, 1.20 equiv) in DMF(20 mL), TosNH2 (1.485 g, 1.10 equiv) was added in, and then theresulting solution was stirred for 0.5 h at 0° C., and stirred foranother 1 h at 25° C., and then the resulting solution was quenched bythe addition of 50 mL of water, extracted with 3×15 mL of EtOAc and theorganic layers combined and concentrated under vacuum. The residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(3:7) to afford 2 g (72%) of the title compound as a light yellow solid.LCMS (ESI, m/z): 353.23 [M+H]⁺.

Step 3: Synthesis of 4-bromo-1H,2H,3H-pyrrolo[3,4-c]pyridinehydrobromide

A solution of4-bromo-2-[(4-methylbenzene)sulfonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine (2g, 5.66 mmol, 1.00 equiv) and Phenol (3.2 g, 6.00 equiv) in 48% HBr/HOAc(5 mL) and acetic acid (10 mL) was stirred for 1 overnight at 90° C.,and then the resulting solution was concentrated under vacuum, and thecrude product purified by re-crystallization from EtOAc to afford 1.4 g(88%) of the title compound as a yellow solid. LCMS (ESI, m/z): 199.05[M+H]⁺.

Step 4: Synthesis of(5-[4-bromo-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of 4-bromo-1H,2H,3H-pyrrolo[3,4-c]pyridine hydrobromide (1.4g, 5.00 mmol, 1.00 equiv),5-chloro-4-(trifluoromethyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydropyridazin-3-one(2.55 g, 7.76 mmol, 1.10 equiv) and TEA (2.15 g, 21.25 mmol, 3.00 equiv)in ethanol (15 mL) was stirred for 2 h at 60° C., and then the resultingsolution was concentrated under vacuum, and then the residue was appliedonto a silica gel column eluting with EtOAc/petroleum ether (4:6) toafford 400 mg (16%) of the title compound as a dark green solid. LCMS(ESI, m/z): 491.38 [M+H]⁺.

Step 5: Synthesis of5-[4-(pyridin-3-ylmethoxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[4-bromo-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(150 mg, 0.31 mmol, 1.00 equiv), (Pd(allyl)C₁)₂ (14 mg, 0.10 equiv),Rockphos (11 mg, 0.10 equiv), pyridin-3-ylmethanol (134 mg, 1.23 mmol,4.00 equiv) and Cs₂CO₃ (200 mg, 0.61 mmol, 2.00 equiv) in toluene (5 mL)was stirred for 2 h at 80° C. under an atmosphere of nitrogen, and thenthe resulting solution was concentrated under vacuum, and then theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (6:4) to afford 80 mg (50%) of the title compoundas yellow oil. LCMS (ESI, m/z): 520.19 [M+H]⁺.

Step 6: Synthesis of5-[4-(pyridin-3-ylmethoxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[4-(pyridin-3-ylmethoxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(200 mg, 0.38 mmol, 1.00 equiv), in HCl/dioxane (5 mL, 4M) was stirredovernight at room temperature, and then the resulting solution wasconcentrated under vacuum, and then the residue was purified byPrep-HPLC yielding the title compound (2.7 mg, 2.0%) as a white solid.LCMS (ESI, m/z): 390.15 [M+H]+, ¹HNMR (DMSO-d₆, 400 MHz) δ 8.71 (d,J=1.6 Hz, 1H), 8.54 (dd, J=4.8, 1.6 Hz, 1H), 8.16 (d, J=5.6 Hz, 1H),8.07 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.43 (dd, J=8.4, 4.8 Hz, 1H), 7.13(d, J=5.2 Hz, 1H), 5.51 (s, 2H), 4.97 (d, J=11.6 Hz, 4H).

Example 16:5-[4-(piperidin-4-yloxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of5-[4-bromo-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of (4-bromo-1H,2H,3H-pyrrolo[3,4-c]pyridine hydrobromide (700mg, 2.50 mmol, 1.00 equiv), TEA (1.07 g, 10.57 mmol, 3.00 equiv),5-chloro-4-(trifluoromethyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydropyridazin-3-one(1.25 g, 3.80 mmol, 1.10 equiv) in ethanol (20 mL, 1.00 equiv) wasstirred for 2 h at 60° C. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (4/6) to afford 300 mg (24%) of the title compoundas a dark green solid. LCMS (ESI, m/z): 493.06[M+H]⁺.

Step 2: Synthesis of5-[4-hydroxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[4-bromo-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(440 mg, 0.90 mmol, 1.00 equiv), t-BuBrettphos (65 mg, 0.15 equiv),K₃PO₄ (571 mg, 2.69 mmol, 3.00 equiv), Pd(OAc)₂ (20 mg, 0.09 mmol, 0.10equiv) in dioxane (5 mL) and water (1 mL) was stirred for 1 h at 100° C.The reaction mixture was concentrated under vacuum. The residue wasapplied onto a silica gel column eluting with ethyl DCM/methanol (95/5)to afford 125 mg (33%) of the title compound as a yellow solid. LCMS(ESI, m/z): 429.15 [M+H].

Step 3: Synthesis of Tert-Butyl4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-4-yl]oxy)piperidine-1-carboxylate

A solution of5-[4-hydroxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(115 mg, 0.27 mmol, 1.00 equiv), Ag₂CO₃ (149 mg, 0.54 mmol, 20.00equiv), tert-butyl 4-iodopiperidine-1-carboxylate (168 mg, 0.54 mmol,2.00 equiv) in DMF (10 mL) was stirred for 48 h at 80° C. The resultingsolution was diluted with 20 mL of water and extracted with 3×20 ml ofEtOAc. The organic layers combined, washed with 3×40 mL of brine, driedover Na₂SO₄. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1/1) to afford 146 mg (89%) of the title compoundas yellow oil. LCMS (ESI, m/z): 612.28 [M+H].

Step 4: Synthesis of5-[4-(piperidin-4-yloxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of 5 tert-butyl4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-4-yl]oxy)piperidine-1-carboxylate(146 mg, 0.24 mmol, 1.00 equiv) in methanol (2 mL) and hydrogenchloride/Et2O (10 mL) was stirred for 4 h at room temperature. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN. Then the residue was furtherpurified by Prep-HPLC yielding the title compound (6 mg, 7%) as a brownsolid. LCMS (ESI, m/z): 382.35 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ:12.56 (s, 1H), 8.14-8.03 (m, 2H), 7.04 (d, J=5.3 Hz, 1H), 5.18 (dt,J=9.0, 4.8 Hz, 1H), 4.97-4.94 (m, 2H), 4.88-4.83 (m, 2H), 2.97 (dd,J=11.0, 6.4 Hz, 2H), 2.62 (t, J=10.0 Hz, 2H), 1.94 (dd, J=12.5, 8.1 Hz,2H), 1.60-1.47 (m, 2H).

Example 17:5-(5-[[(pyridin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of5-(5-bromo-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(3.29 g, 10.01 mmol, 1.00 equiv), 5-bromo-2,3-dihydro-1H-isoindolehydrochloride (2.35 g, 10.02 mmol, 1.00 equiv), TEA (2.02 g, 19.96 mmol,2.00 equiv) in ethanol (50 mL) was stirred for 3 hours at 40° C. Thesolvent was concentrated under vacuum and the residue was applied onto asilica gel column eluting with EtOAc/petroleum ether (1/5) to afford3.65 g (74%) of the title compound as a yellow solid. LCMS (ESI, m/z):490.07 [M+H]⁺.

Step 2: Synthesis of2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindole-5-carbonitrile

A solution of5-(5-bromo-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1.3 g, 2.65 mmol, 1 equiv), Pd(PPh₃)₄ (0.6 g, 0.52 mmol, 0.196 equiv),Zn(CN)₂ (0.62 g, 5.28 mmol, 1.991 equiv) in NMP (15 mL) was stirred for2 hours at 120 degrees C. in an oil bath. The reaction was then quenchedby the addition of 20 mL of water. The resulting solution was extractedwith 3×30 ml of EtOAc dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (25/75) to afford 1.8 g crudeof the title compound as yellow oil. LCMS (ESI, m/z): 437.15 [M+H]⁺.

Step 3: Synthesis of5-[5-(aminomethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindole-5-carbonitrile(1 g, 2.29 mmol, 1.00 equiv), Palladium carbon (500 mg), hydrogenchloride (0.2 mL) in ethanol (20 mL) was stirred for 2 days at 30° C.under the atmosphere of hydrogen with the pressure of 30 atm. The solidswere filtered out and the filtration was concentrated under vacuum. Theresidue was applied onto a silica gel column eluting with DCM/methanol(96:4) to afford 700 mg (69%) of the title compound as yellow oil. LCMS(ESI, m/z): 441.19 [M+H]⁺.

Step 4: Synthesis of5-(5-[[(pyridin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[5-(aminomethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(200 mg, 0.45 mmol, 1.00 equiv), Pd₂(dba)₃.CHCl₃ (50 mg, 0.05 mmol, 0.10equiv), Xantphos (28 mg, 0.05 mmol, 0.10 equiv), 4-bromopyridine (152mg, 0.96 mmol, 2.00 equiv), Cs₂CO₃ (315 mg, 2.00 equiv) in dioxane (15mL) was stirred for 2 h at 100° C. in an oil bath under the atmosphereof nitrogen. After concentration the residue was applied onto a silicagel column eluting with DCM/methanol (9:1) to afford 130 mg (55%) of thetitle compound as a yellow solid. LCMS (ESI, m/z): 518.21 [M+H]⁺.

Step 5: Synthesis of5-(5-[[(pyridin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-(5-[[(pyridin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(130 mg, 0.25 mmol, 1.00 equiv) in hydrogen chloride/dioxane (20 mL) wasstirred for 14 h at room temperature. The resulting mixture wasconcentrated under vacuum. The pH value of the solution was adjusted to9 with saturated sodium bicarbonate aqueous. The resulting solution wasextracted with DCM and the organic layers combined and dried overanhydrous sodium sulfate. After concentration the residue was appliedonto a silica gel column eluting with DCM/methanol (9:1). Then theresidue was further purified by Prep-HPLC yielding the title compound(35.7 mg 37%) as a white solid. LCMS (ESI, m/z): 388.13 [M+H]⁺, ¹HNMR(DMSO-d₆, 400 MHz) δ: 12.52 (s, 1H), 8.00 (d, J=5.2 Hz, 3H), 7.38-7.27(m, 3H), 7.25 (t, J=6.1 Hz, 1H), 6.54-6.48 (m, 2H), 4.95 (d, J=9.1 Hz,4H), 4.36 (d, J=6.1 Hz, 2H).

Example 18 Isomer A:6-[4-[(3-[[(1R)-2-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrileand Example 18 Isomer B:6-[4-[(3-[[(1S)-2-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1:5-[1-(Hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-chloro-4-(trifluoromethyl)-2-[2-(trimethylsilyl)ethoxy]methyl-2,3-dihydropyridazin-3-one(Int-A6, 4.8 g, 14.60 mmol, 1.00 equiv),2,3-dihydro-1H-isoindol-1-ylmethanol hydrochloride (2.7 g, 14.54 mmol,1.00 equiv) and TEA (4.4 g, 43.48 mmol, 2.99 equiv) in ethanol (100 mL)was stirred for 1 h at 60° C., and then the resulting solution wasconcentrated under vacuum and the residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (45:55) to afford 2.9 g (45%)of the title compound as a brown solid. LCMS: [M+H]⁺ 442.17.

Step 2: Methyl3-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoate

Under nitrogen, a solution of5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(2.93 g, 6.64 mmol, 1.00 equiv), methyl 3-bromobenzoate (2.84 g, 13.21mmol, 1.99 equiv), Pd(allyl)Cl₂ (243 mg), Rockphos (311 mg) and Cs₂CO₃(4.3 g, 13.20 mmol, 1.99 equiv) in Toluene (100 mL) was stirred for 18 hat 80° C. The resulting solution was concentrated under vacuum and thenthe residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1:3) to afford 3 g (79%) of the title compound asa brown solid. LCMS: [M+H]⁺ 576.21.

Step 3:3-([2-[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoicAcid

A solution of methyl 3-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoate(1.15 g, 2.00 mmol, 1.00 equiv) and LiOH (240 mg, 10.02 mmol, 5.02equiv) in THF (12 mL) and water (3 mL) was stirred for 3 h at 60° C. Theresulting solution was concentrated under vacuum and the residue wasdiluted with 10 mL of H₂O, and then the pH value of the solution wasadjusted to 5 with HCl (36.5%). The solid was collected by filtration toafford 1.1 g (98%) of the title compound as a light yellow solid. LCMS:[M+H]⁺ 562.19.

Step 4:3-([2-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoicAcid

A solution of3-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoicacid (1.1 g, 1.96 mmol, 1.00 equiv) in HCl/dioxane (20 mL, 4M) wasstirred for 3 h at RT, and then the resulting solution was concentratedunder vacuum to afford 1 g of the title compound as a crude brown solid.LCMS: [M+H]⁺ 432.11.

Step 5:6-[4-[(3-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(3-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoicacid (500 mg, 1.16 mmol, 1.00 equiv), HATU (528 mg, 1.39 mmol, 1.20equiv), DIPEA (449 mg, 3.47 mmol, 3.00 equiv) and Int-A4 (240 mg, 1.27mmol, 1.1 equiv) in DMF (5 mL) was stirred for 2 h at RT. Afterconcentration by reduced pressure, the resulting solution was purifiedby C18 reverse phase chromatography eluting with H₂O/ACN.

The residue was further purified by Prep-HPLC and Chiral-Prep-HPLC(CHIRAL Repaired IA, 5 μm, 0.46×10 cm column, eluting with a gradient of(Hexanes:DCM=3:1) (0.1% DEA):EtOH=50:50, at a flow rate of 1 mL/min)yielding the title compounds as white solids. The absolutestereochemistry was assigned based on a protein X-ray crystal structureobtained of Example 18 Isomer B which confirmed (S)-absolutestereochemistry and was observed to be the more potent enantiomer.

Example 18 Isomer A

153.2 mg, 22%, LCMS: [M+H]⁺ 602.05, ¹H NMR (300 MHz, Methanol-d₄) δ 8.43(d, J=1.8 Hz, 1H), 8.42 (s, 1H), 7.79 (dd, J=9.0, 2.4 Hz, 1H), 7.53-7.50(m, 1H), 7.41-7.35 (m, 4H), 7.05-6.99 (m, 2H), 6.94-6.87 (m, 2H), 6.20(s, 1H), 5.33 (d, J=14.8 Hz, 1H), 4.68 (d, J=14.7 Hz, 1H), 4.53 (dd,J=10.2, 3.3 Hz, 1H), 4.29 (dd, J=10.2, 6.6 Hz, 1H), 3.91-3.44 (m, 8H).tR=4.369 min.

Example 18 Isomer B

153.3 mg, 22%, ¹H NMR (300 MHz, Methanol-d₄) δ 8.43 (d, J=1.8 Hz, 1H),8.38 (s, 1H), 7.79 (dd, J=9.0, 2.4 Hz, 1H), 7.52-7.50 (m, 1H), 7.41-7.35(m, 4H), 7.04-6.99 (m, 2H), 6.94-6.87 (m, 2H), 6.19 (s, 1H), 5.32 (d,J=14.7 Hz, 1H), 4.67 (d, J=14.7 Hz, 1H), 4.53 (dd, J=10.2, 3.6 Hz, 1H),4.26 (dd, J=10.2, 6.6 Hz, 1H), 3.92-3.41 (m, 8H). LCMS: [M+H]⁺ 602.05.tR=5.955 min.

Example 19:5-[5-fluoro-6-[2-(morpholin-4-yl)ethoxy]-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of5-[5-fluoro-6-[2-(morpholin-4-yl)ethoxy]-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-(5-fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(200 mg, 0.45 mmol, 1 equiv), 4-(2-chloroethyl)morpholine hydrochloride(99.6 mg, 0.54 mmol, 1.192 equiv), K₂CO₃ (123.6 mg, 0.89 mmol, 1.992equiv) in DMF (10 mL) was stirred for 12 h at 80° C. The reaction wasthen quenched by the addition of 5 mL of water. The resulting solutionwas extracted with 3×15 ml of EtOAc and the organic layers combined anddried over anhydrous sodium sulfate. The organic layers concentratedunder vacuum. The residue was applied onto a silica gel column elutingwith EtOAc/petroleum ether (90/10) to afford 180 mg (72%) of the titlecompound as yellow oil. LCMS (ESI, m/z): 559.23 [M+H]⁺.

Step 2: Synthesis of5-[5-fluoro-6-[2-(morpholin-4-yl)ethoxy]-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[5-fluoro-6-[2-(morpholin-4-yl)ethoxy]-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (180 mg, 0.32 mmol, 1equiv) in HCl/dioxane (10 mL) was stirred for 12 h at room temperature.After concentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN. Then the residue was furtherpurified by Prep-HPLC yielding the title compound (52.1 mg, 37.8%) as awhite solid. LCMS (ESI, m/z): 429.38 [M+H]⁺, ¹HNMR (DMSO-d₆, 300 MHz) δ:12.55 (s, 1H), 7.98 (s, 1H), 7.27 (m, 2H), 4.91 (m, 4H), 4.18 (t, J=5.7Hz, 2H), 3.64-3.54 (m, 4H), 3.31 (m, 2H), 2.73 (t, J=5.7 Hz, 2H), 2.48(m, 2H).

Example 20:5-[5-fluoro-6-(piperidin-4-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of Tert-Butyl4-[([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)methyl]piperidine-1-carboxylate

A solution of5-(5-fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1 g, 2.24 mmol, 1.00 equiv), potassium carbonate (3.1 g, 22.43 mmol,10.00 equiv), tert-butyl 4-(iodomethyl)piperidine-1-carboxylate (4.4 g,13.53 mmol, 6.00 equiv) in DMF (15 mL) was stirred for 1.5 h at 80° C.The solution was quenched with 50 ml water, then the resulting solutionwas extracted with EtOAc (3×60 mL) and the organic layers combined. Thesolution was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (5/95) to afford 1 g (69%) of the title compoundas a white solid. LCMS (ESI, m/z): 643.30 [M+H]⁺.

Step 2: Synthesis of5-[5-fluoro-6-(piperidin-4-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of tert-butyl4-[([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)methyl]piperidine-1-carboxylate(200 mg, 0.31 mmol, 1.00 equiv), trifluoroacetic acid (2 mL) in DCM (10mL) was stirred for 3 h at room temperature. After concentration, theresidue was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN. Then the residue was further purified by Prep-HPLC yieldingthe title compound (24.2 mg, 19%) as a white solid. LCMS (ESI, m/z):413.10 [M+H]⁺, ¹HNMR (DMSO-d₆, 300 MHz) δ 7.98 (d, J=13.8 Hz, 1H),7.28-7.18 (m, 2H), 4.90-4.88 (m, 4H), 3.87 (dd, J=6.4, 3.9 Hz, 2H),3.01-2.95 (m, 2H), 2.45-2.44 (m, 2H), 1.84 (d, J=4.2 Hz, 1H), 1.75-1.58(m, 2H), 1.22-1.13 (m, 2H).

Example 21:5-[5-[(1-acetylpiperidin-4-yl)methoxy]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[5-fluoro-6-(piperidin-4-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(325.35 mg, 0.79 mmol, 1.00 equiv), TEA (227.25 mg, 2.25 mmol, 4.00equiv), Ac₂O (45.9 mg, 0.45 mmol, 1.00 equiv) in DCM (15 mL) was stirredfor 2 h at room temperature. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN.Then the residue was further purified by Prep-HPLC yielding the titlecompound (68.2 mg, 19%) as a white solid. LCMS (ESI, m/z): 455.05[M+H]⁺, ¹HNMR (Methanol-d₄, 300 MHz) δ 8.04 (s, 1H), 7.14 (dd, J=9.2,4.7 Hz, 2H), 5.00-4.99 (s, 4H), 4.59 (d, J=12.9 Hz, 1H), 4.06-3.84 (m,3H), 3.25-3.13 (m, 1H), 2.80-2.56 (m, 1H), 2.13 (s, 3H), 2.12-2.11 (m,1H), 2.04-1.84 (m, 2H), 1.50-1.22 (m, 2H).

Example 22:5-[5-fluoro-6-[(1-methylpiperidin-4-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[5-fluoro-6-(piperidin-4-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(150 mg, 0.36 mmol, 1.00 equiv), (HCHO)_(n) (62.1 mg, 3.00 equiv),acetic acid (0.5 mL), NaBH₃CN (43.47 mg, 0.69 mmol, 3.00 equiv) inmethanol (15 mL) was stirred for 15 h at room temperature. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN. Then the residue was furtherpurified by Prep-HPLC yielding the title compound (57.9 mg, 37%) as awhite solid. LCMS (ESI, m/z): 427.10 [M+H]⁺, ¹HNMR (Methanol-d4, 300MHz) δ 8.04 (s, 1H), 7.12 (dd, J=9.2, 4.5 Hz, 2H), 4.96 (s, 4H) 3.93 (d,J=5.7 Hz, 2H), 2.95 (d, J=11.5 Hz, 2H), 2.31 (s, 3H), 2.11 (t, J=6.3 Hz,2H), 1.98-1.81 (m, 3H), 1.65-1.26 (m, 2H).

Example 23:5-(5-fluoro-6-[[(piperidin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindole-5-carbonitrile

A solution of 6-fluoro-2,3-dihydro-1H-isoindole-5-carbonitrile (600 mg,3.70 mmol, 1 equiv),5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1.45 g, 4.41 mmol, 1.192 equiv), TEA (1.12 g, 11.07 mmol, 2.991 equiv)in EtOH (15 mL) was stirred for 2 h at 80° C. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (15/85) to afford 1.2 g (71%)of the title compound as a yellow solid. LCMS (ESI, m/z): 455.14 [M+H]⁺.

Step 2: Synthesis of5-[5-(aminomethyl)-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindole-5-carbonitrile(3 g, 6.60 mmol, 1 equiv), Pd/C (300 mg, 2.82 mmol, 0.427 equiv) in EtOH(30 mL) was stirred 7 days at room temperature with an atmosphere ofhydrogen. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with DCM/methanol (93/7) to afford 1.58 g (52.2%) of thetitle compound as a yellow solid. LCMS (ESI, m/z): 459.18 [M+H]⁺.

Step 3: Synthesis of Tert-Butyl4-[([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]methyl)amino]piperidine-1-carboxylate

A solution of5-[5-(aminomethyl)-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(200 mg, 0.44 mmol, 1 equiv), tert-butyl 4-oxopiperidine-1-carboxylate(104.6 mg, 0.52 mmol, 1.204 equiv), NaBH₃CN (137.34 mg, 2.19 mmol, 5.010equiv) in MeOH (10 mL) was stirred for 2 h at room temperature. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford 100 mg (35.7%) of thetitle compound as yellow oil. LCMS (ESI, m/z): 642.30 [M+H]⁺.

Step 4: Synthesis of5-(5-fluoro-6-[[(piperidin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of tert-butyl4-[([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]methyl)amino]piperidine-1-carboxylate(100 mg, 0.16 mmol, 1 equiv) in HCl/dioxane (12 mL) was stirred for 12 hat room temperature. After concentration, the residue was purified byC18 reverse phase chromatography eluting with H₂O/CH₃CN. Then theresidue was further purified by Prep-HPLC yielding the title compound(20.4 mg, 31.8%) as a white solid. LCMS (ESI, m/z): 412.40 [M+H]⁺, ¹HNMR(300 MHz, DMSO-d₆) δ: 8.01 (s, 1H), 7.48 (d, J=6.7 Hz, 1H), 7.21 (d,J=10.0 Hz, 1H), 4.95 (s, 4H), 3.77 (s, 2H), 2.91 (d, J=12.0 Hz, 2H),2.47-2.33 (m, 3H), 1.77 (d, J=11.9 Hz, 2H), 1.13 (m, 2H).

Example 24:5-(5-[[(1-acetylpiperidin-4-yl)amino]methyl]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

Step 1: Synthesis of5-(5-[[(1-acetylpiperidin-4-yl)amino]methyl]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[5-(aminomethyl)-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(300 mg, 0.65 mmol, 1 equiv), 1-acetylpiperidin-4-one (110.6 mg, 0.78mmol, 1.197 equiv), NaBH₃CN (206 mg, 3.28 mmol, 5.01 equiv) in MeOH (10mL) was stirred 2 h at room temperature. After concentration, theresidue was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN to afford 250 mg (65.5%) of the title compound as yellow oil.LCMS (ESI, m/z): 584.26 [M+H]⁺.

Step 2: Synthesis of5-(5-[[(1-acetylpiperidin-4-yl)amino]methyl]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-(5-[[(1-acetylpiperidin-4-yl)amino]methyl]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(250 mg, 0.43 mmol, 1 equiv) in HCl/dioxane (12 mL) was stirred for 12 hat room temperature. After concentration, the residue was purified byC18 reverse phase chromatography eluting with H₂O/CH₃CN. Then theresidue was further purified by Prep-HPLC yielding the title compound(70.3 mg, 36.2%) as a white solid. LCMS (ESI, m/z): 454.43 [M+H]⁺, ¹HNMR(300 MHz, DMSO-d₆) δ: 12.56 (s, 1H), 8.01 (s, 1H), 7.49 (d, J=6.8 Hz,1H), 7.21 (d, J=10.0 Hz, 1H), 4.95 (s, 4H), 4.14 (d, J=13.1 Hz, 1H),3.78 (s, 2H), 3.78-3.72 (m, 1H), 3.05 (t, J=11.3 Hz, 1H), 2.79-2.56 (m,2H), 2.38-2.22 (m, 1H), 1.99 (s, 3H), 1.88-1.72 (m, 2H), 1.33-1.12 (m,2H).

Example 25:5-(5-fluoro-6-[[(1-methylpiperidin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

Step 1: Synthesis of5-(5-fluoro-6-[[(1-methylpiperidin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[5-(aminomethyl)-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(300 mg, 0.65 mmol, 1 equiv), 1-methylpiperidin-4-one (89.4 mg, 0.79mmol, 1.208 equiv), NaBH₃CN (206.01 mg, 3.28 mmol, 5.010 equiv) in MeOH(10 mL) was stirred 2 h at room temperature. After concentration, theresidue was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN to afford 200 mg (55%) of the title compound as yellow oil.LCMS (ESI, m/z): 556.27 [M+H]⁺.

Step 2: Synthesis of5-(5-fluoro-6-[[(1-methylpiperidin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-(5-fluoro-6-[[(1-methylpiperidin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(200 mg, 0.36 mmol, 1 equiv) in HCl/dioxane (12 mL) was stirred for 12 hat room temperature. After concentration, the residue was purified byC18 reverse phase chromatography eluting with H₂O/CH₃CN. Then theresidue was further purified by Prep-HPLC yielding the title compound(41.0 mg, 26.8%) as a white solid. LCMS (ESI, m/z): 426.42 [M+H]⁺, ¹HNMR(300 MHz, DMSO-d₆) δ: 12.52 (s, 1H), 7.97 (s, 1H), 7.44 (d, J=6.8 Hz,1H), 7.17 (d, J=10.0 Hz, 1H), 4.92 (s, 4H), 3.72 (s, 2H), 2.66 (d,J=11.2 Hz, 2H), 2.34-2.24 (m, 1H), 2.10 (s, 3H), 1.89-1.70 (m, 5H),1.34-1.16 (m, 2H).

Example 26:5-[5-fluoro-6-(morpholin-4-yl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of5-[5-fluoro-6-(morpholin-4-yl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-(5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(300 mg, 0.59 mmol, 1 equiv), morpholine (62 mg, 0.71 mmol, 1.206equiv), Pd₂(dba)₃ (108 mg, 0.12 mmol, 0.200 equiv), Xantphos (68.2 mg,0.12 mmol, 0.200 equiv), t-BuOK (131.7 mg, 1.17 mmol, 1.989 equiv) inToluene (10 mL) was stirred for 12 h at 80° C. with an inert atmosphereof nitrogen. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (25/75) to afford 170 mg (56%) of the titlecompound as a yellow solid. LCMS (ESI, m/z): 515.20 [M+H]⁺.

Step 2: Synthesis of5-[5-fluoro-6-(morpholin-4-yl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[5-fluoro-6-(morpholin-4-yl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(170 mg, 0.33 mmol, 1 equiv) in HCl/dioxane (10 mL) was stirred for 12 hat room temperature. After concentration, the residue was purified byC18 reverse phase chromatography eluting with H₂O/CH₃CN. Then theresidue was further purified by Prep-HPLC yielding the title compound(20.7 mg, 16.3%) as a white solid. LCMS (ESI, m/z): 385.33 [M+H]⁺, ¹HNMR(DMSO-d₆, 300 MHz) δ 12.54 (s, 1H), 7.98 (s, 1H), 7.22 (d, J=12.4 Hz,1H), 7.08 (d, J=8.0 Hz, 1H), 4.91 (br, 4H), 3.79-3.68 m, 4H), 3.04-2.94(m, 4H).

Example 27:5-(4-[[1-(diphenylmethyl)piperidin-4-yl]oxy]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of Tert-Butyl4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)piperidine-1-carboxylate

A solution of5-(4-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1.1 g, 2.57 mmol, 1.00 equiv), potassium carbonate (1.8 g, 13.02 mmol,5.00 equiv), tert-butyl 4-iodopiperidine-1-carboxylate (4.0 g, 12.86mmol, 5.00 equiv) in DMF (30 mL) was stirred for 3 days at 80° C. in anoil bath. After concentration, the residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (1:3) to afford 1.3 g (83%) ofthe title compound as a yellow solid. LCMS (ESI, m/z): 611.28 [M+H]⁺.

Step 2: Synthesis of5-[4-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of tert-butyl4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)piperidine-1-carboxylate(600 mg, 0.98 mmol, 1.00 equiv) in hydrogen chloride/dioxane (120 ml,1M) was stirred for 12 h at room temperature. After concentration, theresidue was applied onto a silica gel column eluting with DCM/methanol(2:1) to afford 270 mg (54%) of the title compound as a yellow solid.LCMS (ESI, m/z): 511.23 [M+H]⁺.

Step 3: Synthesis of5-(4-[[1-(diphenylmethyl)piperidin-4-yl]oxy]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[4-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(250 mg, 0.49 mmol, 1.00 equiv), TEA (99 mg, 0.98 mmol, 2.00 equiv),[bromo(phenyl)methyl]benzene (241 mg, 0.98 mmol, 2.00 equiv) in dioxane(8 mL) was stirred for 2 days at 100° C. in an oil bath. Afterconcentration, the residue was applied onto a silica gel column elutingwith EtOAc/petroleum ether (1:3) to afford 154 mg (46%) of the titlecompound as a solid. LCMS (ESI, m/z): 677.31 [M+H]⁺.

Step 4: Synthesis of5-(4-[[1-(diphenylmethyl)piperidin-4-yl]oxy]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-(4-[[1-(diphenylmethyl)piperidin-4-yl]oxy]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(154 mg, 0.23 mmol, 1.00 equiv) in hydrogen chloride/dioxane (15 mL) wasstirred for 12 h at room temperature. After concentration, the residuewas applied onto a silica gel column with DCM/methanol (2:1) and thecrude product was purified by Prep-HPLC yielding the title compound(15.7 mg 13%) as a white solid. LCMS (ESI, m/z): 547.22 [M+H]⁺, ¹H NMR(DMSO-d₆, 300 MHz) δ: 12.51 (s, 1H), 8.01 (s, 1H), 7.41 (d, J=7.4 Hz,4H), 7.31-7.15 (m, 7H), 6.97-6.90 (dd, J=14.1, 7.9 Hz, 2H), 4.95 (s,2H), 4.84 (s, 2H), 4.53-4.49 (dr, 1H), 4.35 (s, 1H), 2.58-2.51 (m, 2H),2.27-2.22 (m, 2H), 1.93-1.91 (dr, 2H), 1.74-1.68 (dr, 2H).

Example 28:5-(5-[[1-(diphenylmethyl)piperidin-4-yl]oxy]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of 1-(diphenylmethyl)piperidin-4-ol

A solution of piperidin-4-ol (5 g, 49.43 mmol, 1.00 equiv), TEA (5 g,49.41 mmol, 1.00 equiv), [bromo(phenyl)methyl]benzene (9 g, 36.42 mmol,0.80 equiv) in THF (30 mL) was stirred for 2 days at room temperature.After concentration, the residue was applied onto a silica gel columneluting with EtOAc/petroleum ether (1:2) to afford 3.8 g (29%) of thetitle compound as a solid. LCMS (ESI, m/z): 268.16 [M+H]⁺.

Step 2: Synthesis of 1-(diphenylmethyl)piperidin-4-yl methanesulfonate

A solution of 1-(diphenylmethyl)piperidin-4-ol (3.8 g, 14.21 mmol, 1.00equiv), MsCl (1.44 g, 1.10 equiv), TEA (1.52 g, 15.02 mmol, 2.00 equiv)in DCM (20 mL) was stirred for 30 min at room temperature. The resultingsolution was extracted with of DCM and the organic layers combined andconcentrated under vacuum to afford 3.2 g (65%) of the title compound asa yellow solid. LCMS (ESI, m/z): 346.14 [M+H]⁺.

Step 3: Synthesis of5-(5-[[1-(diphenylmethyl)piperidin-4-yl]oxy]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-(5-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(400 mg, 0.94 mmol, 1.00 equiv), potassium carbonate (1.3 g, 9.41 mmol,10.00 equiv), 1-(diphenylmethyl)piperidin-4-yl methanesulfonate (649 mg,1.88 mmol, 2.00 equiv) in DMF (40 mL) was stirred for 2 days at 80° C.in an oil bath. After concentration, the residue was applied onto asilica gel column eluting with EtOAc/petroleum ether (1:3) to afford 200mg (32%) of the title compound as a yellow solid. LCMS (ESI, m/z):677.31 [M+H]⁺.

Step 4: Synthesis of5-(5-[[1-(diphenylmethyl)piperidin-4-yl]oxy]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-(5-[[1-(diphenylmethyl)piperidin-4-yl]oxy]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(200 mg, 0.30 mmol, 1.00 equiv) in hydrogen chloride/dioxane (20 mL) wasstirred for 12 h at room temperature. The residue was applied onto asilica gel column eluting with EtOAc/petroleum ether (1:2). The crudeproduct was purified by Prep-HPLC yielding the title compound (14.3 mg9%) as a white solid. LCMS (ESI, m/z): 547.22 [M+H]⁺, ¹H NMR(Methanol-d₄, 300 MHz) δ: 8.02 (s, 1H), 7.45-7.42 (d, J=7.8 Hz, 4H),7.31-7.14 (m, 7H), 6.92-6.87 (m, 2H), 4.97-4.94 (d, J=8.4 Hz, 4H), 4.41(dr, 1H), 4.29 (s, 1H), 2.72 (dr, 2H), 2.27-2.21 (m, 2H), 2.03-1.97 (m,2H), 1.78-1.71 (m, 2H).

Example 29:6-(4-[[3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)phenyl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1: Synthesis of 5-[(2-hydroxyethyl)(methyl)amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1 g, 3.04 mmol, 1.00 equiv), TEA (600 mg, 5.93 mmol, 2.00 equiv),2-(methylamino)ethan-1-ol (1.1 g, 14.65 mmol, 5.00 equiv) in ethanol (14mL) was stirred for 2 h at 60° C. in an oil bath. The resulting mixturewas concentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (8:1) to afford 1.1 g (98%) ofthe title compound as yellow oil. LCMS (ESI, m/z): 368.15 [M+H]⁺.

Step 2: Synthesis of methyl3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)benzoate

A solution of5-[(2-hydroxyethyl)(methyl)amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(800 mg, 2.18 mmol, 1.00 equiv), [Pd(allyl)Cl]₂ (80 mg, 0.22 mmol, 0.10equiv), rockphos (102 mg, 0.22 mmol, 0.10 equiv), Cs₂CO₃ (1.4 g, 4.30mmol, 2.00 equiv), methyl 3-bromobenzoate (466 mg, 2.17 mmol, 1.00equiv) in toulene (12 mL) was stirred for 2 h at 85 degrees C. in an oilbath. The resulting mixture was concentrated under vacuum. The residuewas applied onto a silica gel column eluting with EtOAc/petroleum ether(3:2) to afford 700 mg (64%) of the title compound as a yellow solid.LCMS (ESI, m/z): 502.19 [M+H]⁺.

Step 3: Synthesis of methyl3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)benzoate

A solution of methyl3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)benzoate(700 mg, 1.40 mmol, 1.00 equiv) in hydrogen chloride/dioxane (30 mL) wasstirred for 14 h at room temperature. The resulting mixture wasconcentrated under vacuum to afford 600 mg crude of the title compoundas yellow oil. LCMS (ESI, m/z): 372.11 [M+H]⁺.

Step 4: Synthesis of3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)benzoicAcid

A solution of methyl3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)benzoate(700 mg, 1.89 mmol, 1 equiv), LiOH.H₂O (553 mg, 13.18 mmol, 6.990 equiv)in methanol (10 mL) was stirred for 4 h at room temperature. Theresulting solution was extracted with 2×20 ml of EtOAc and the aqueouscombined. The pH value of the solution was adjusted to 2 with HCl (10%).The solids were collected by filtration to afford 380 mg (56. %) of thetitle compound as a yellow solid. LCMS (ESI, m/z): 358.09 [M+H]⁺.

Step 5: Synthesis of6-(4-[[3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)phenyl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)benzoicacid (100 mg, 0.28 mmol, 1 equiv), HATU (111 mg, 0.29 mmol, 1.043equiv), DIPEA (108 mg, 0.84 mmol, 2.986 equiv), Int-A4 (58.1 mg, 0.31mmol, 1.103 equiv) in DMF (2 mL) was stirred for 1 h at roomtemperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN. Then the residuewas further purified by Prep-HPLC yielding the title compound (98.0 mg,66.4%) as a white solid. LCMS (ESI, m/z): 528.50 [M+H]⁺, ¹H NMR (300MHz, DMSO-d₆) δ: 12.51 (s, 1H), 8.52 (d, J=2.3 Hz, 1H), 8.06 (s, 1H),7.90 (d, J=9.1, 2.4 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.05-6.89 (m, 4H),4.26 (t, J=5.0 Hz, 2H), 3.86 (t, J=5.1 Hz, 2H), 3.62-3.52 (m, 6H), 3.33(m, 2H), 3.10 (d, J=2.3 Hz, 3H).

Example 30 Isomer A:(R)-4-(Trifluoromethyl)-5-(1-((3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)phenoxy)methyl)isoindolin-2-yl)pyridazin-3(2H)-oneand Example 30 Isomer B:(S)-4-(Trifluoromethyl)-5-(1-((3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)phenoxy)methyl)isoindolin-2-yl)pyridazin-3(2H)-one

A solution of3-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoicacid (300 mg, 0.70 mmol, 1.00 equiv), HATU (278 mg, 0.73 mmol, 1.05equiv), DIPEA (269 mg, 2.08 mmol, 3.00 equiv), and Int-A18 (161 mg, 0.70mmol, 1.00 equiv) in DCM (2 mL) was stirred overnight at 25° C. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/ACN. The residue was further purified byPrep-HPLC and Chiral-Prep-HPLC (CHIRALPAK IA-3, 3 μm, 0.46×5 cm column,eluting with a gradient of MtBE (10 mM NH₃):EtOH=80:20, at a flow rateof 1 mL/min) yielding the title compounds as yellow solids. The absolutestereochemistry was assigned based on a protein X-ray crystal structureobtained of Example 18 Isomer B which confirmed (S)-absolutestereochemistry and was observed to be the more potent enantiomer (seeTable A-1).

Example 30 Isomer A

76.1 mg, 42%, LCMS: [M+H]⁺ 645.20, ¹H NMR (400 MHz, Methanol-d₄) δ8.40-8.39 (d, J=3.5 Hz, 2H), 7.78-7.76 (dd, J=9.1, 2.6 Hz, 1H),7.53-7.51 (m, 1H), 7.42-7.37 (m, 4H), 7.05-7.00 (m, 2H), 6.94-6.92 (m,2H), 6.20 (dr, 1H), 5.33-5.29 (d, J=14.7 Hz, 1H), 4.68-4.64 (d, J=14.8Hz, 1H), 4.54-4.50 (dd, J=10.3, 3.5 Hz, 1H), 4.29-4.25 (dd, J=10.2, 6.8Hz, 1H), 3.83-3.53 (m, 8H). tR=1.562 min.

Example 30 Isomer B

76.1 mg, 42%, LCMS: [M+H]⁺ 645.20, tR=1.562 min.

Example 31:6-[4-[(3-[[(2R)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(15 g, 45.62 mmol, 1 equiv), (2R)-pyrrolidin-2-ylmethanol (4.6 g, 45.48mmol, 0.997 equiv), TEA (14 g, 138.35 mmol, 3.033 equiv) in EtOH (200mL) was stirred for 4 h at 60° C. The resulting mixture was concentratedunder vacuum. The residue was crystallized with Et₂O to afford 8.6 g(47.9%) of the title compound as a white solid. LCMS (ESI, m/z): 394.17[M+H]⁺.

Step 2: Synthesis of methyl3-[[(2R)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate

A solution of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(8.6 g, 21.86 mmol, 1 equiv), methyl 3-bromobenzoate (5.2 g, 24.18 mmol,1.106 equiv), Rockphos (1.02 g, 2.18 mmol, 0.100 equiv), Cs₂CO₃ (14.2 g,43.58 mmol, 1.994 equiv), Pd₂(allyl)₂Cl₂ (0.798 g, 2.18 mmol, 0.100equiv) in Toluene (100 mL) was stirred for 12 h at 80° C. with an inertatmosphere of nitrogen. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (20/80) to afford 7.1 g (61.6%) of the titlecompound as yellow oil. LCMS (ESI, m/z): 528.21 [M+H]⁺.

Step 3: Synthesis of methyl3-[[(2R)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate

A solution of3-[[(2R)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate(9.1 g, 17.25 mmol, 1 equiv) in HCl/dioxane (100 mL) was stirred for 12h at room temperature. The resulting mixture was concentrated undervacuum to afford 9.5 g (crude) of the title compound as yellow oil. LCMS(ESI, m/z): 398.12 [M+H]⁺.

Step 4: Synthesis of3-[[(2R)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicAcid

A solution of3-[[(2R)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate(1.5 g, 3.78 mmol, 1 equiv), LiOH.H₂O (0.795 g, 18.94 mmol, 5.0 equiv)in MeOH (30 mL) was stirred for 4 h at room temperature. The resultingsolution was extracted with 3×30 ml of EtOAc. The pH value of thesolution was adjusted to 2 with HCl (12 M). The solids were collected byfiltration to afford 600 mg (41%) of the title compound as a whitesolid. LCMS (ESI, m/z): 384.11 [M+H]⁺.

Step 5: Synthesis of6-[4-[(3-[[(2R)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-[[(2R)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicacid (100 mg, 0.26 mmol, 1 equiv), HATU (103.7 mg, 0.27 mmol, 1.045equiv), DIPEA (100.6 mg, 0.78 mmol, 2.984 equiv), Int-A4 (54 mg, 0.29mmol, 1.100 equiv) in DMF (2 mL) was stirred for 2 h at roomtemperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN. Then the residuewas further purified by Prep-HPLC yielding the title compound (76.9 mg,53%) as a white solid. LCMS (ESI, m/z): 554.54 [M+H]⁺, ¹HNMR (DMSO-d₆,300 MHz) δ: 12.44 (s, 1H), 8.53 (d, J=2.3 Hz, 1H), 8.15 (s, 1H), 7.91(dd, J=9.1, 2.4 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 6.98 (dd, J=18.8, 8.6Hz, 4H), 4.83 (s, 1H), 4.15 (dd, J=10.4, 4.0 Hz, 1H), 4.04 (dd, J=10.3,6.0 Hz, 1H), 3.67-3.48 (m, 9H), 3.30 (d, J=8.9 Hz, 1H), 2.23 (s, 1H),1.99 (d, J=6.7 Hz, 1H), 1.93-1.81 (m, 2H).

Example 32:6-[4-[(3-[[(2S)-1-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1:5-[(2S)-2-(Hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(10 g, 30.41 mmol, 1.00 equiv), TEA (13.4 g, 132.42 mmol, 3.00 equiv),(S)-pyrrolidin-2-ylmethanol (3.4 g, 33.61 mmol, 1.10 equiv) in ethanol(60 mL) was stirred for 2 h at 60° C. The resulting mixture wasconcentrated under vacuum and the residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (26:74) to afford 5 g (42%) ofthe title compound. LCMS (ESI, m/z): 394.18 [M+H]+.

Step 2: Synthesis of methyl3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate

A solution of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1 g, 2.54 mmol, 1.00 equiv), [Pd(allyl)Cl]₂ (93 mg, 0.10 equiv),Rockphos (119 mg, 0.10 equiv), Cs₂CO₃ (2.5 g, 7.67 mmol, 3.00 equiv),methyl 3-bromobenzoate (1.09 g, 5.07 mmol, 2.00 equiv) in toluene (80mL) was stirred for 20 h at 80° C. The solvent was concentrated undervacuum and the residue was applied onto a silica gel column eluting withEtOAc/hexane (1:1) to afford 969 mg (72%) of the title compound as abrown oil. LCMS (ESI, m/z): 528.22 [M+H]⁺.

Step 3: Synthesis of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicAcid

A solution of methyl3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate(969 mg, 1.84 mmol, 1.00 equiv), LiOH (220 mg, 9.19 mmol, 5.00 equiv),water (4 mL) in methanol (20 mL) was stirred for 3 h at roomtemperature. The pH value of the solution was adjusted to 5 withhydrogen chloride. The solvent was concentrated under vacuum and theresidue was applied onto a silica gel column eluting with EtOAc/hexane(1:1) to afford 900 mg (95%) of the title compound as a brown solid.LCMS (ESI, m/z): 514.20 [M+H]⁺.

Step 4: Synthesis of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicAcid

A solution3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicacid (900 mg, 1.75 mmol, 1.00 equiv) in hydrogen chloride/dioxane (30mL) was stirred for 3 h at room temperature. After concentration, theresidue was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN to afford 600 mg (89%) of the title compound as a yellowsolid. LCMS (ESI, m/z): 384.12 [M+H]⁺.

Step 5: Synthesis of6-[4-[(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicacid (200 mg, 0.52 mmol, 1.00 equiv), HATU (239.4 mg, 0.63 mmol, 1.20equiv), DIPEA (205.11 mg, 1.59 mmol, 3.00 equiv), Int-A4 nitrile (118.44mg, 0.63 mmol, 1.20 equiv) in DMF (3 mL) was stirred for 3 h at roomtemperature. After concentration, The residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN yielding the titlecompound (132.9 mg, 46%) as a white solid. LCMS (ESI, m/z): 554.05[M+H]⁺, ¹HNMR (300 MHz, Methanol-d₄) δ 8.44 (s, 1H), 8.24 (s, 1H), 7.78(dd, J=9.1, 2.4 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.17-7.00 (m, 2H),7.00-6.84 (m, 2H), 4.86 (d, J=4.1 Hz, 1H), 4.25 (dd, J=10.3, 3.7 Hz,1H), 4.07 (dd, J=10.3, 6.9 Hz, 1H), 3.98-3.62 (m, 7H), 3.61-3.37 (m,3H), 2.47-2.25 (m, 1H), 2.07 (dd, J=11.4, 5.7 Hz, 1H), 1.88-1.84 (m,2H).

Example 33:6-[3-(hydroxymethyl)-4-[(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl4-(5-cyanopyridin-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate

A solution of tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate (780mg, 3.61 mmol, 1.20 equiv), 6-chloropyridine-3-carbonitrile (520 mg,3.75 mmol, 1.00 equiv), DIPEA (780 mg, 6.04 mmol, 2.00 equiv) in NMP (15mL) was stirred for 8 h at 100° C. The resulting solution was quenchedwith water. The resulting solution was extracted with of EtOAc and theorganic layers combined. After concentrated under vacuum. The residuewas applied onto a silica gel column with EtOAc/petroleum ether (1:1) toafford of 900 mg (75%) of the title compound as a solid. LCMS (ESI,m/z): 319.18 [M+H]⁺.

Step 2: Synthesis of6-[3-(hydroxymethyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of tert-butyl4-(5-cyanopyridin-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (900mg, 2.83 mmol, 1.00 equiv) in hydrogen chloride/dioxane (15 mL) wasstirred for 0.5 h at room temperature. The resulting mixture wasconcentrated under vacuum to afford 600 mg of the title compound as asolid. LCMS (ESI, m/z): 219.15 [M+H]⁺.

Step 3: Synthesis of6-[3-(hydroxymethyl)-4-[(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicacid (114.9 mg, 0.30 mmol, 1.00 equiv), HATU (136.8 mg, 0.36 mmol, 1.20equiv), DIPEA (116.1 mg, 0.90 mmol, 3.00 equiv),6-[3-(hydroxymethyl)piperazin-1-yl]pyridine-3-carbonitrile (78.48 mg,0.36 mmol, 1.20 equiv) in DMF (3 mL) was stirred for 3 h at roomtemperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN. Then the residuewas further purified by Prep-HPLC yielding the title compound (35.2 mg,20%) as a white solid. LCMS (ESI, m/z): 584.10 [M+H]⁺, ¹HNMR (300 MHz,Methanol-d4) δ 8.50 (s, 1H), 8.24 (d, J=5.0 Hz, 1H), 7.77 (dd, J=9.1,2.4 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.07-6.86 (m, 4H), 4.87-4.83 (m,2H), 4.54 (s, 2H), 4.37-3.89 (m, 3H), 3.72-3.41 (m, 3H), 3.44 (t, J=8.9Hz, 2H), 3.28-3.01 (m, 2H), 2.49-2.22 (m, 1H), 2.07 (dd, J=11.2, 5.6 Hz,1H), 2.00-1.69 (m, 2H).

Example 34:6-[2-oxo-4-[(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl4-(5-cyanopyridin-2-yl)-3-oxopiperazine-1-carboxylate

A solution of tert-butyl 3-oxopiperazine-1-carboxylate (2.0 g, 10.00mmol, 1.00 equiv), tripotassium phosphate (4.24 g, 20.00 mmol, 2.00equiv), CuI (95.0 mg, 0.50 mmol, 0.05 equiv),6-bromopyridine-3-carbonitrile (1.82 g, 10.00 mmol, 1.00 equiv),(1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (142.0 mg, 1.00 mmol,0.10 equiv) in dioxane (80 mL) was stirred for 3 h at 110° C. Theresulting mixture was concentrated under vacuum and the residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(6:1) to afford 1.2 g (40%) of the title compound as a white solid. LCMS(ESI, m/z): 303.15 [M+H]⁺.

Step 2: Synthesis of 6-(2-oxopiperazin-1-yl)pyridine-3-carbonitrile

A solution of tert-butyl4-(5-cyanopyridin-2-yl)-3-oxopiperazine-1-carboxylate (200 mg, 0.66mmol, 1.00 equiv) in hydrogen chloride/dioxane (20 mL) was stirred for0.5 h at room temperature. The resulting mixture was concentrated undervacuum to afford 170 mg crude of the title compound as a white solid.LCMS (ESI, m/z): 203.10[M+H]⁺.

Step 3: Synthesis of6-[2-oxo-4-[(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicacid (300 mg, 0.78 mmol, 1.00 equiv), HATU (296.4 mg, 0.78 mmol, 1.20equiv), DIPEA (251.55 mg, 1.95 mmol, 3.00 equiv),6-(2-oxopiperazin-1-yl)pyridine-3-carbonitrile (131.3 mg, 0.65 mmol,1.20 equiv) in DMF (3 mL, 3.00 equiv) was stirred for 2 h at roomtemperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN. Then the residuewas further purified by Prep-HPLC yielding the title compound (7.9 mg,2%) as a white solid. LCMS (ESI, m/z): 568.20 [M+H]⁺, ¹HNMR (300 MHz,Chloroform-d) δ 10.69 (s, 1H), 8.68 (d, J=2.3 Hz, 1H), 8.36 (d, J=8.9Hz, 1H), 8.08-7.79 (m, 2H), 7.49-7.29 (m, 1H), 7.05 (d, J=7.6, 1.2 Hz,1H), 6.99 (d, J=2.1 Hz, 2H), 4.64 (dd, J=6.0, 4.8 Hz, 1H), 4.48 (s, 2H),4.23 (s, 2H), 4.11 (dd, J=9.8, 4.2 Hz, 1H), 4.06-3.56 (m, 4H), 3.45 (dd,J=10.9, 6.0 Hz, 1H), 2.40 (t, J=6.3 Hz, 1H), 2.19-2.00 (m, 1H),1.95-1.72 (m, 2H).

Example 35: 6-[4-[(4-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(4-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of methyl4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoate

A solution of5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(440 mg, 1.00 mmol, 1.00 equiv), [Pd(allyl)Cl]₂ (37 mg, 0.10 mmol, 0.10equiv), Rockphos (47 mg, 0.10 mmol, 0.10 equiv), Cs2CO3 (970 mg, 2.98mmol, 2.00 equiv), and methyl 4-bromobenzoate (430 mg, 2.00 mmol, 2.00equiv) in Toluene (10 mL) was stirred for 5 h at 80° C. The reaction wasthen quenched by the addition of 150 mL of water. The resulting mixturewas concentrated under vacuum. The residue was applied onto a silica gelcolumn with EtOAc/petroleum ether (1/4) to afford 470 mg (82%) of thetitle compound as yellow oil. LCMS (ESI, m/z): 576.21 [M+H]⁺.

Step 2: Synthesis of4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoic

A solution of methyl 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoate(470 mg, 0.82 mmol, 1.00 equiv), water (2 mL), and LiOH (100 mg, 4.18mmol, 5.00 equiv) in THF (8 mL) was stirred for 1 overnight at 60° C.under N2 (g) atmosphere. The pH value of the solution was adjusted to5-6 with hydrogen chloride (6 M). The resulting solution was extractedwith 2×200 mL of EtOAc and the organic layers combined and concentratedunder vacuum, to afford 400 mg (87%) of the title compound as a yellowsolid. LCMS (ESI, m/z): 562.19 [M+H]⁺.

Step 3: Synthesis of4-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoic

A solution of4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoicacid (400 mg, 0.71 mmol, 1.00 equiv) in hydrogen chloride/dioxane (20mL) was stirred for 1 overnight at 25° C. The resulting mixture wasconcentrated under vacuum to afford 300 mg (98%) of the title compoundas a black solid. LCMS (ESI, m/z): 432.11 [M+H]⁺.

Step 4: Synthesis of6-[4-[(4-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile,and6-[4-[(4-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of4-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoicacid (350 mg, 0.81 mmol, 1.00 equiv), Int-A4 (153 mg, 0.81 mmol, 1.00equiv), DIPEA (300 mg, 2.32 mmol, 3.00 equiv), and HATU (313 mg, 0.82mmol, 1.01 equiv) in DMF (3 mL) was stirred for 1 h at 25° C. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN. Then Chiral-Prep-HPLC yielding(after arbitrary assignment of the stereochemistry) the title compounds,respectively, isomer A 54.1 mg (54%) as a yellow solid. LCMS (ESI, m/z):602.20 [M+H]⁺, ¹H NMR (400 MHz, Methanol-d₄) δ 8.44-8.39 (m, 2H),7.79-7.76 (dd, J=9.1, 2.4 Hz, 1H), 7.54-7.51 (d, J=5.8 Hz, 1H),7.43-7.37 (td, J=5.5, 5.0, 2.0 Hz, 5H), 6.98-6.96 (m, 2H), 6.91-6.88 (m,1H), 6.21 (s, 1H), 5.33-5.29 (d, J=14.7 Hz, 1H), 4.67-4.62 (m, 1H),4.55-4.52 (dd, J=10.4, 3.5 Hz, 1H), 4.31-4.27 (dd, J=10.3, 6.8 Hz, 1H),3.79-3.50 (m, 8H). tR=3.517 min (CHIRALPAK IG-3, 0.46*10 cm; 3 um, MtBE(0.1% DEA):EtOH=70:30, 1.0 mL/min) and isomer B 48.6 mg (49%) as ayellow solid. LCMS (ESI, m/z): 602.20 [M+H]⁺, tR=3.515 min (CHIRALPAKIG-3, 0.46*10 cm; 3 um, MtBE (0.1% DEA):EtOH=70:30, 1.0 mL/min).

Example 36:6-[4-[(2-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]pyridin-4-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(2-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]pyridin-4-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of methyl2-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-4-carboxylate

A solution of5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(441 mg, 1.00 mmol, 1.00 equiv), [Pd(allyl)Cl]₂ (36.6 mg, 0.10 mmol,0.10 equiv), Rockphos (46.8 mg, 0.10 mmol, 0.10 equiv), Cs₂CO₃ (65.2 mg,0.20 mmol, 2.00 equiv), methyl 2-bromopyridine-4-carboxylate (430 mg,1.99 mmol, 2.00 equiv) in toluene (10 mL) was stirred for 3 h at 80° C.The solvent was concentrated under vacuum and the residue was appliedonto a silica gel column eluting with EtOAc/petroleum ether (3:7) toafford 420 mg (73%) of the title compound as a yellow solid. LCMS (ESI,m/z): 577.21 [M+H]⁺.

Step 2: Synthesis of2-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-4-carboxylicAcid

A solution of methyl 2-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-4-carboxylate(420 mg, 0.73 mmol, 1.00 equiv), LiOH (87.6 mg, 3.66 mmol, 5.00 equiv),water (2 ml) in methanol (10 ml) was stirred for 3 h at roomtemperature. The pH value of the solution was adjusted to 5 withhydrogen chloride. The solvent was concentrated under vacuum and theresidue was applied onto a silica gel column eluting withacetate/petroleum ether (2:1) to afford 300 mg (73%) of the titlecompound as a solid. LCMS (ESI, m/z): 563.20 [M+H]⁺.

Step 3: Synthesis of2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-4-carboxylicAcid

A solution of2-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-4-carboxylicacid (300 mg, 0.52 mmol, 1.00 equiv) in hydrogen chloride/dioxane (20mL) was stirred for 2 h at room temperature. After concentration, theresidue was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN to afford 261 mg crude of the title compound as a solid. LCMS(ESI, m/z): 433.11 [M+H]⁺.

Step 4: Synthesis of6-[4-[(2-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]pyridin-4-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(2-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]pyridin-4-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-4-carboxylicacid (261 mg, 0.60 mmol, 1.00 equiv), HATU (277.4 mg, 0.73 mmol, 1.20equiv), DIPEA (309.6 mg, 2.40 mmol, 4.00 equiv), Int-A4 (136.3 mg, 0.72mmol, 1.20 equiv) in DMF (3 mL) was stirred for 2 h at room temperature.After concentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN. Then the residue was furtherpurified by Prep-HPLC and Chiral-Prep-HPLC yielding the title compounds.The absolute stereochemistry was assigned based on a protein X-raycrystal structure obtained of Example 18 Isomer B which confirmed(S)-absolute stereochemistry and was observed to be the more potentenantiomer.

Example 36 Isomer A

(11 mg, 20%) as a white solid. LCMS (ESI, m/z): 603.10 [M+H]+, ¹HNMR(Methanol-d4, 300 MHz) δ: 8.45 (d, J=2.1 Hz, 1H), 8.35 (s, 1H), 8.25 (d,J=5.2 Hz, 1H), 7.79 (dd, J=9.1, 2.4 Hz, 1H), 7.50 (d, J=4.2 Hz 1H), 7.40(d, J=2.0 Hz, 3H), 7.02 (dd, J=5.2, 1.3 Hz, 1H), 6.92 (d, J=8.9 Hz, 1H),6.74 (s, 1H), 6.18 (t, J=2.1 Hz, 1H), 5.24 (d, J=14.7 Hz, 1H), 4.84 (d,J=4.2 Hz, 1H), 4.75-4.71 (m, 1H), 4.70-4.64 (m, 1H), 3.86 (s, 4H),3.74-3.68 (m, 2H), 3.61-3.49 (m, 2H). tR=2.208 min (CHIRALPAK IG-3,0.46*5 cm; 3 um, Hex:DCM=1:1 (0.1% DEA):EtOH=30:70, 1.0 mL/min)

Example 36 Isomer B

(10.7 mg, 10%) as a white solid. LCMS (ESI, m/z): 603.10 [M+H]⁺.tR=2.947 min(CHIRALPAK IG-3, 0.46*5 cm; 3 um, Hex:DCM=1:1 (0.1%DEA):EtOH=30:70, 1.0 mL/min).

Example 37:5-[[(2S)-1-(3-Oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)butan-2-yl]oxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1:3-[(2S)-2-Hydroxybutoxy]-1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propan-1-one

A solution of Int-20 (1 g, 3.49 mmol, 1 equiv), (2S)-butane-1,2-diol(1574.1 mg, 17.47 mmol, 5 equiv), and Cs₂CO₃ (2276.4 mg, 6.99 mmol, 2.00equiv) in MeCN (10 mL) was stirred for 4 h at 75° C. The resultingsolution was diluted with 300 mL of DCM. The resulting mixture waswashed with 45 mL×2 of H₂O and 45 mL×2 of saturated sodium chlorideaqueous solution. The residue was applied onto a silica gel column withDCM/EtOAc (1/1) to afford 1.16 g (81.2%) of the title compound as yellowsolids. LCMS (ESI, m/z): 377.37 [M+H]⁺

Step 2:2-[(4-Methoxyphenyl)methyl]-5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)butan-2-yl]oxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of3-[(2S)-2-hydroxybutoxy]-1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propan-1-one(0.37 g, 0.98 mmol, 1 equiv), Cs₂CO₃ (0.64 g, 1.96 mmol, 2 equiv), and5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(0.939 g, 1.96 mmol, 3.00 equiv) in MeCN (6 mL) was stirred for 18 h at80° C. The resulting solution was diluted with 300 mL of EtOAc. Theresulting mixture was washed with 45 mL×2 of water and 45 mL×2 ofsaturated sodium chloride, then dried over anhydrous sodium sulfate andconcentrated. The residue was applied onto a silica gel column withEtOAc/petroleum ether (2/3) to afford 0.28 g (32.0%) of the titlecompound as white solids. LCMS (ESI, m/z): 721.85 [M+H]⁺

Step 3:5-[[(2S)-1-(3-Oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)butan-2-yl]oxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of2-[(4-methoxyphenyl)methyl]-5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)butan-2-yl]oxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(0.27 g, 0.410 mmol, 1 equiv), and H₂SO₄ (0.402 g, 4.1 mmol, 10 equiv)in TFA (7 mL) was stirred for 3 days at 25° C. The reaction mixture wascooled with a water/ice bath. The resulting solution was diluted with300 mL of DCM. The resulting mixture was washed with 45 mL x 2 of waterand 45 mL×2 of saturated sodium chloride aqueous solution, then driedover anhydrous sodium sulfate and concentrated. The residue was purifiedby C18 reverse phase chromatography eluting with H₂O/CH₃CN yielding thetitle compound (16.1 mg, 33.7%) as white solids. LCMS (ESI, m/z): 539.25[M+H]⁺, ¹H-NMR (400 MHz, DMSO-d₆) δ: 13.22 (s, 1H), 8.74 (s, 2H), 8.28(s, 1H), 5.01 (d, J=6.7 Hz, 1H), 3.86-3.75 (m, 4H), 3.76-3.58 (m, 3H),3.54-3.50 (m, 5H), 2.55 (d, J=6.3 Hz, 2H), 1.71-1.58 (m, 2H), 0.91 (t,J=7.4 Hz, 3H).

Example 38 Isomer A:6-[4-[(2-[[(1S)-2-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]pyrimidin-4-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrileand Example 38 Isomer B:6-[4-[(2-[[(1R)-2-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]pyrimidin-4-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Methyl2-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrimidine-4-carboxylate

A solution of5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(500 mg, 1.13 mmol, 1.00 equiv), (Pd(allyl)C₁)₂ (53 mg, 0.10 equiv),Rockphos (41 mg, 0.10 equiv), Cs₂CO₃ (1.1 mg, 3.00 equiv), methyl2-chloropyrimidine-4-carboxylate (292 mg, 1.69 mmol, 1.50 equiv) intoluene (10 mL) under nitrogen condition was stirred for overnight at85° C. The solvent was concentrated under vacuum and the residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(1/1) to afford 420 mg (64%) of the title compound as a yellow solid.LCMS (ESI, m/z): 578.20 [M+H]⁺

Step 2: Synthesis of methyl2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrimidine-4-carboxylate

A solution of methyl 2-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrimidine-4-carboxylate(420 mg, 0.73 mmol, 1.00 equiv) in dioxane/HCl (20 mL, 4 M) was stirredfor overnight at 25° C. The solvent was concentrated under vacuum toafford 300 mg (92%) of the title compound as yellow oil. LCMS (ESI,m/z): 448.12 [M+H]⁺

Step 3: Synthesis of2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrimidine-4-carboxylicAcid

A solution of methyl2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrimidine-4-carboxylate(400 mg, 0.89 mmol, 1.00 equiv), LiOH.H₂O (200 mg, 4.77 mmol, 5.00equiv) in MeOH (10 mL) and water (2 mL) was stirred for 2 h at 25° C.The resulting solution was concentrated under vacuum. The residue wasdiluted with 3 mL of water, then the pH value of the solution wasadjusted to 2 with hydrochloric acid and the solid was filtered toafford 215 mg (55%) of the title compound as a pink solid. LCMS (ESI,m/z): 434.10 [M+H]⁺

Step 4: Synthesis of6-[4-[(2-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]pyrimidin-4-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(2-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]pyrimidin-4-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrimidine-4-carboxylicacid (100 mg, 0.23 mmol, 1.00 equiv), HOBT (47 mg, 0.35 mmol, 1.50equiv), EDCI (67 mg, 0.35 mmol, 1.50 equiv), DIPEA (90 mg, 0.70 mmol,3.00 equiv), Int-A4 (87 mg, 0.46 mmol, 2.00 equiv) in DMF (3 mL) wasstirred for overnight at 25° C. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN.Then the residue was further purified by Prep-HPLC and Chiral-Prep-HPLCyielding the title compounds. The absolute stereochemistry was assignedbased on a protein X-ray crystal structure obtained of Example 18 IsomerB which confirmed (S)-absolute stereochemistry and was observed to bethe more potent enantiomer.

Isomer A (6.1 mg, 23%) as a white solid. LCMS (ESI, m/z): 604.20 [M+H]+,1H NMR (300 MHz, DMSO-d6) δ: 12.57 (s, 1H), 8.69 (d, J=4.9 Hz, 1H), 8.51(d, J=2.3 Hz, 1H), 8.31 (s, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.48 (s, 1H),7.38 (d, J=9.9 Hz, 3H), 7.28 (d, J=4.9 Hz, 1H), 6.92 (d, J=9.0 Hz, 1H),6.14 (s, 1H), 5.04 (d, J=14.4 Hz, 1H), 4.90 (d, J=11.8 Hz, 1H),4.71-4.41 (m, 2H), 3.97-3.55 (m, 6H), 3.40 (m, 2H). tR=4.448 min(CHIRALPAK IC-3, 0.46*10 cm; 3 um, MtBE (0.1% DEA):EtOH=80:20, 1.0mL/min) and isomer B (6.4 mg, 25%) as a white solid. LCMS (ESI, m/z):604.20 [M+H]⁺, tR=5.550 min (CHIRALPAK IC-3, 0.46*10 cm; 3 um, MtBE(0.1% DEA):EtOH=80:20, 1.0 mL/min).

Example 39:6-[4-([3-[2-([2-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]phenyl]carbonyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of5-[4-(2-hydroxyethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-(4-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(2 g, 4.68 mmol, 1.00 equiv), potassium carbonate (3.2 g, 23.15 mmol,5.00 equiv), 2-bromoethan-1-ol (2.9 g, 23.21 mmol, 5.00 equiv) in DMF(30 mL, 5.00 equiv) was stirred for 12 h at 80° C. in an oil bath. Thereaction mixture was diluted with H₂O (200 mL). The resulting solutionwas extracted with EtOAc (4×100 mL) and the organic layers werecombined. After concentration, the residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (1:4) to afford 1.35 g (61%)of the title compound as a yellow solid. LCMS (ESI, m/z): 472.18 [M+H]⁺

Step 2: Synthesis of methyl3-[2-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]benzoate

Under nitrogen, a solution of5-[4-(2-hydroxyethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(675 mg, 1.43 mmol, 1.00 equiv), [Pd(allyl)Cl]₂ (67 mg, 0.10 equiv),Rockphos (52 mg, 0.10 equiv), CS₂CO₃ (932 mg, 2.86 mmol, 2.00 equiv),methyl 3-bromobenzoate (612 mg, 2.85 mmol, 2.00 equiv) in Toluene (10mL) was stirred for 12 h at 80° C. in an oil bath. After filtration, thefiltrate was concentrated under reduced pressure. The residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(1:1) to afford 624 mg (72%) of the title compound as a yellow solid.LCMS (ESI, m/z): 606.22 [M+H]⁺

Step 3: Synthesis of methyl4-[2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]benzoate

A solution of methyl4-[2-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]benzoate(624 mg, 1.03 mmol, 1.00 equiv) in hydrogen chloride/dioxane (20 mL) wasstirred for 12 h at room temperature. After concentration, the residuewas applied onto a silica gel column eluting with EtOAc/petroleum ether(1:2) to afford 400 mg (82%) of the title compound as a yellow solid.LCMS (ESI, m/z): 476.22 [M+H]⁺

Step 4: Synthesis of4-[2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]benzoicAcid

A solution of methyl4-[2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]benzoate(400 mg, 0.84 mmol, 1.00 equiv), LiOH (120 mg, 5.01 mmol, 5.00 equiv) inMeOH (5 mL) and water (1 mL) was stirred for 2 h at room temperature.The pH value of the solution was adjusted to 3 with hydrogen chloride.The solids were collected by filtration to afford 260 mg (67%) of thetitle compound as a gray solid. LCMS (ESI, m/z): 462.12 [M+H]⁺

Step 5: Synthesis of6-[4-([3-[2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]phenyl]carbonyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-[2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]benzoicacid (260 mg, 0.56 mmol, 1.00 equiv), HATU (232 mg, 0.61 mmol, 1.00equiv), DIPEA (315 mg, 2.44 mmol, 4.00 equiv), Int-A4 (115 mg, 0.61mmol, 1.00 equiv) in DMF (2 mL) was stirred for 30 min at roomtemperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN yielding the titlecompound (89.8 mg, 25%) as a white solid. LCMS (ESI, m/z): 632.22[M+H]⁺, ¹H NMR (Methanol-d₄, 400 MHz) δ: 8.43-8.41 (d, J=2.3 Hz, 1H),8.03 (s, 1H), 7.77-7.74 (dd, J=9.1, 2.3 Hz, 1H), 7.44-7.30 (dt, J=25.9,7.9 Hz, 2H), 7.14-6.95 (m, 5H), 6.89-6.86 (d, J=9.0 Hz, 1H), 5.02-4.98(m, 2H), 4.92-4.88 (m, 2H), 4.47-4.43 (m, 4H), 3.91-3.53 (m, 8H).

Example 40:6-(4-[[3-([1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]piperidin-2-yl]methoxy)phenyl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1: Synthesis of5-[2-(hydroxymethyl)piperidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(2 g, 6.08 mmol, 1.00 equiv), piperidin-2-ylmethanol (772.3 mg, 6.71mmol, 1.10 equiv) and TEA (1.35796 g, 13.42 mmol, 2.00 equiv) in ethanol(40 mL) was stirred for 2 h at 60° C., and then the resulting solutionwas concentrated under vacuum, and then the residue was applied onto asilica gel column eluting with EtOAc/petroleum ether (3:1) to afford 639mg (26%) of the title compound as yellow oil. LCMS (ESI, m/z): 408.19[M+H]⁺.

Step 2: Synthesis of methyl3-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]piperidin-2-yl]methoxy)benzoate

A solution of5-[2-(hydroxymethyl)piperidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(560 mg, 1.37 mmol, 1.00 equiv), Pd(allyl)Cl₂ (50.3616 mg, 0.10 equiv),Rockphos (64.5344 mg, 0.10 equiv), Cs₂CO₃ (1.3457 g, 4.13 mmol, 3.00equiv) and methyl 3-bromobenzoate (586.176 mg, 2.73 mmol, 2.00 equiv) intoluene (5 mL) was stirred for 12 h at 80° C. under in atmosphere ofnitrogen, and then the resulting solution was concentrated under vacuum,and then the residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1:2) to afford 153 mg (21%) of the title compoundas a light brown solid. LCMS (ESI, m/z): 542.23 [M+H]⁺.

Step 3: Synthesis of3-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]piperidin-2-yl]methoxy)benzoicAcid

A solution of methyl3-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]piperidin-2-yl]methoxy)benzoate(153 mg, 0.28 mmol, 1.00 equiv) and LiOH (33.9 mg, 1.42 mmol, 5.00equiv) in methanol (6 mL) and water (2 mL) was stirred for 24 h at roomtemperature, and then the residue was concentrated under vacuum, andthen diluted with 3 mL of water, and then the pH value of the resultingsolution was adjusted to 4 by HCl (1M), and then the residue solutionwas concentrated under vacuum to afford 107 mg of the title compound asa crude light yellow solid. LCMS(ESI, m/z): 528.21 [M+H]⁺

Step 4: Synthesis of3-([1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]piperidin-2-yl]methoxy)benzoicAcid

A solution of3-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]piperidin-2-yl]methoxy)benzoicacid (125 mg, 0.24 mmol, 1.00 equiv) in hydrogen chloride/dioxane (5 mL,4M) was stirred for 2 h at room temperature, and then the resultingsolution was concentrated under vacuum to afford 116 mg of the titlecompound as a crude yellow oil. LCMS (ESI, m/z): 398.12 [M+H]⁺

Step 5: Synthesis of6-(4-[[3-([1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]piperidin-2-yl]methoxy)phenyl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of3-([1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]piperidin-2-yl]methoxy)benzoicacid (69 mg, 0.17 mmol, 1.00 equiv), HATU (66.0 mg, 0.17 mmol, 1.00equiv), DIPEA (67.4 mg, 0.52 mmol, 3.00 equiv) and Int-A4 (39.2 mg, 0.22mmol, 1.20 equiv) in DMF (2 mL) was stirred for 4 h at room temperature,and then the resulting solution was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN, then the crude product wasfurther purified by Prep-HPLC yielding the title compound (26.7 mg,27.0%) as a white solid. LCMS (ESI, m/z): 568.25[M+H]⁺, ¹HNMR (CD₃OD-d₄,300 MHz) δ 8.43 (d, J=2.1 Hz, 1H), 7.99 (s, 1H), 7.79 (dd, J=9.0, 2.1Hz, 1H), 7.35 (t, J=8.4 Hz, 1H), 7.02 (d, J=7.2 Hz, 1H), 6.92-6.83 (m,3H), 4.54 (t, J=9.9 Hz, 1H), 4.37 (d, J=3.9 Hz, 1H), 4.15 (dd, J=10.2,3.6 Hz, 1H), 3.92-3.50 (m, 9H), 3.43-3.37 (m, 1H), 2.03-1.59 (m, 6H).

Example 41:6-(4-[[3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)phenyl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1: Synthesis of methyl3-(2-[[(tert-butoxy)carbonyl]amino]ethoxy)benzoate

A solution of methyl 3-hydroxybenzoate (760 mg, 5.00 mmol, 1 equiv),tert-butyl N-(2-bromoethyl)carbamate (1679.1 mg, 7.49 mmol, 1.500equiv), K₂CO₃ (1380.7 mg, 9.99 mmol, 2 equiv) in DMF (5 mL) was stirredfor 2 h at 80° C. The resulting solution was extracted with 3×30 ml ofEtOAc and the organic layers combined. The resulting solution wasextracted with 3×30 mL of NaCl(aq) and the organic layers combined andconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (21/79) to afford 1.323 g(89.68%) of the title compound as white oil. LCMS (ESI, m/z): 296.14[M+H]⁺

Step 2: Synthesis of 3-(2-[[(tert-butoxy)carbonyl]amino]ethoxy)benzoicAcid

A solution of methyl 3-(2-[[(tert-butoxy)carbonyl]amino]ethoxy)benzoate(1.223 g, 4.14 mmol, 1.00 equiv), sodium hydroxide (830 mg, 20.75 mmol,5.00 equiv) in methanol (5 mL) was stirred for 2 h at room temperature.The resulting mixture was concentrated under vacuum. The pH value of thesolution was adjusted to 6 with hydrogen chloride (40%). The solids werecollected by filtration. This resulted in 531 mg (46%) of the titlecompound as a white solid. LCMS (ESI, m/z): 282.13 [M+H]⁺

Step 3: Synthesis of Tert-ButylN-[2-(3-[[4-(5-cyanopyridin-2-yl)piperazin-1-yl]carbonyl]phenoxy)ethyl]carbamate

A solution of 3-(2-[[(tert-butoxy)carbonyl]amino]ethoxy)benzoic acid(531 mg, 1.89 mmol, 1.00 equiv), DIPEA (731 mg, 5.66 mmol, 3.00 equiv),HATU (790 mg, 2.08 mmol, 1.10 equiv), Int-A4 (466 mg, 2.07 mmol, 1.10equiv) in DMF (5 mL) was stirred for 8 h at room temperature. Theresulting solution was extracted with 3×30 mL of EtOAc and the organiclayers combined. The resulting solution was extracted with 3×30 mL ofsaturated sodium chloride aqueous and the organic layers combined anddried over anhydrous sodium sulfate and concentrated under vacuum. Thisresulted in 1.142 g (crude) of the title compound as yellow oil. LCMS(ESI, m/z): 452.22 [M+H]⁺

Step 4: Synthesis of6-(4-[[3-(2-aminoethoxy)phenyl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrileHydrochloride

A solution of tert-butylN-[2-(3-[[4-(5-cyanopyridin-2-yl)piperazin-1-yl]carbonyl]phenoxy)ethyl]carbamate(1.142 g) in HCl/dioxane (5 mL) was stirred for 30 min at roomtemperature. The resulting mixture was concentrated under vacuum toafford 0.980 g of the title compound as a yellow solid. LCMS (ESI, m/z):352.17 [M+H]⁺

Step 5: Synthesis of6-(4-[[3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)phenyl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(758 mg, 2.31 mmol, 1 equiv),6-(4-[[3-(2-aminoethoxy)phenyl]carbonyl]piperazin-1-yl)pyridine-3-carbonitriledihydrochloride (980 mg, 2.31 mmol, 1 equiv), TEA (700 mg, 6.93 mmol, 3equiv) in EtOH (5 mL) was stirred for 3 h at 60° C. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column eluting with EtOAc/petroleum ether (93/7) to afford615 mg (41.4%) of the title compound as yellow oil. LCMS (ESI, m/z):644.26 [M+H]⁺

Step 6: Synthesis of6-(4-[[3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)phenyl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-(4-[[3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)phenyl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile(300 mg) in DCM (5 mL) and TFA (1 mL) was stirred for 2 h at roomtemperature. The reaction was then quenched by the addition of 5 mL ofNaHCO₃(aq). The resulting solution was extracted with 3×30 ml of DCM andthe organic layers combined. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN.Then the residue was further purified by Prep-HPLC yielding the titlecompound (61.9 mg, 25.9%) as a white solid. LCMS (ESI, m/z): 514.17[M+H]⁺, ¹H NMR (300 MHz, DMSO-d6) δ: 12.50 (s, 1H), 8.53 (dd, J=2.4, 0.6Hz, 1H), 8.01 (s, 1H), 7.91 (dd, J=9.1, 2.4 Hz, 1H), 7.39 (dd, J=8.4,7.4 Hz, 1H), 7.16 (d, J=3.5 Hz, 1H), 7.07-6.90 (m, 4H), 4.18 (t, J=5.4Hz, 2H), 3.81-3.57 (m, 8H), 3.51 (m, 2H).

Example 42:6-(4-[[3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)phenyl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1: Synthesis of5-(2-bromoethoxy)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(4 g, 12.17 mmol, 1.00 equiv), 2-bromoethan-1-ol (1.66 g, 13.28 mmol,1.10 equiv) and Cs₂CO₃ (7.95 g, 24.32 mmol, 2.00 equiv) in DMF (15 mL)was stirred for 2 h at room temperature, and then the residue wasdissolved in 50 mL of H₂O, extracted with 3×50 mL of EtOAc and theorganic layers combined, washed with 1×50 mL of brine, dried overanhydrous sodium sulfate and concentrated under vacuum, and then theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (35/65) to afford 2.0 g (39%) of the titlecompound as yellow oil. LCMS (ESI, m/z): 417.04 [M+H]⁺.

Step 2: Synthesis of methyl3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]ethoxy)benzoate

A solution of5-(2-bromoethoxy)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1 g, 2.40 mmol, 1.00 equiv), methyl 3-hydroxybenzoate (730 mg, 4.80mmol, 2.00 equiv) and Cs₂CO₃ (1.567 g, 4.79 mmol, 2.00 equiv) in DMF (25mL) was stirred for 3 h at 60° C., and then the residue was dissolved in60 mL of H2O, extracted with 3×60 mL of EtOAc and the organic layerscombined, washed with 1×60 mL of brine, dried over anhydrous sodiumsulfate and concentrated under vacuum, and then the residue was appliedonto a silicagel column eluting with EtOAc/petroleum ether (27/73) toafford 302 mg (26%) of the title compound as yellow oil. LCMS (ESI,m/z): 489.16 [M+H]⁺.

Step 3: Synthesis of methyl3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)benzoate

A solution of methyl3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]ethoxy)benzoate(330 mg, 0.68 mmol, 1.00 equiv) in HCl/dioxane (13 mL, 4M) was stirredfor 1 h at room temperature, and then the resulting solution wasconcentrated under vacuum to afford 280 mg of crude the title compoundas yellow oil. LCMS (ESI, m/z): 359.08[M+H]⁺.

Step 4: Synthesis of3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)benzoicAcid

A solution of methyl3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)benzoate(300 mg, 0.84 mmol, 1.00 equiv) and LiOH (60.3 mg, 2.52 mmol, 3.00equiv) in water (2 mL) and THF (10 mL) was stirred for 2 h at roomtemperature, and then the resulting solution was concentrated undervacuum, and then the residue was diluted with 10 mL of H2O, and then thepH value of the solution was adjusted to 4 with hydrogen chloride (36%),and then the resulting solution was concentrated under vacuum to afford255 mg of the title compound as a crude yellow solid. LCMS (ESI, m/z):345.06 [M+H]⁺.

Step 5: Synthesis of6-(4-[[3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)phenyl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)benzoicacid (230 mg, 0.67 mmol, 1.00 equiv), HATU (254 mg, 0.67 mmol, 1.00equiv), DIPEA (258 mg, 2.00 mmol, 3.00 equiv) and Int-A4 (125 mg, 0.66mmol, 1.00 equiv) in DMF (8 mL) was stirred for 40 min at roomtemperature, and then the resulting solution was purified by C18 reversephase chromatography eluting with H₂O/CH₃CN. After concentration, theresidue was further purified by Prep-HPLC yielding the title compound(11.8 mg 3%) as a white solid. LCMS (ESI, m/z): 515.15 [M+H]⁺, ¹HNMR(DMSO-d₆, 400 MHz,) δ 13.56 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.32 (s,1H), 7.91 (dd, J=9.2, 2.4 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.06-7.00 (m,3H), 6.94 (d, J=9.2 Hz, 1H), 4.78-4.76 (m, 2H), 4.36-4.34 (m, 2H),3.77-3.69 (m, 8H).

Example 43:6-[4-([4-[2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]phenyl]carbonyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of methyl4-[2-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]benzoate

Under nitrogen, a solution of5-[4-(2-hydroxyethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(675 mg, 1.43 mmol, 1.00 equiv), [Pd(allyl)Cl]₂ (67 mg, 0.10 equiv),Rockphos (52 mg, 0.10 equiv), CS₂CO₃ (932 mg, 2.86 mmol, 2.00 equiv),methyl 4-bromobenzoate (612 mg, 2.85 mmol, 2.00 equiv) in Toluene (10mL) was stirred for 12 h at 80° C. in an oil bath. After filtration, thefiltrate was concentrated under reduced pressure. the residue wasapplied onto a silica gel column with EtOAc/petroleum ether (1:1) toafford 430 mg (50%) of the title compound as a yellow solid. LCMS (ESI,m/z): 606.22 [M+H]⁺

Step 2: Synthesis of methyl4-[2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]benzoate

A solution of methyl4-[2-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]benzoate(430 mg, 0.71 mmol, 1.00 equiv) in hydrogen chloride/dioxane (20 mL) wasstirred for 12 h at room temperature. The resulting mixture wasconcentrated under vacuum to afford 300 mg (89%) of the title compoundas a yellow solid. LCMS (ESI, m/z): 476.14 [M+H]⁺

Step 3: Synthesis of4-[2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]benzoicAcid

A solution of methyl4-[2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]benzoate(300 mg, 0.63 mmol, 1.00 equiv), LiOH (76 mg, 3.17 mmol, 5.00 equiv) inMeOH (5 mL) and water (1 mL) was stirred for 2 h at room temperature.The pH value of the solution was adjusted to 3 with hydrogen chloride.The solids were collected by filtration to afford 250 mg (86%) of thetitle compound as a gray solid. LCMS (ESI, m/z): 462.12 [M+H]⁺

Step 4: Synthesis of6-[4-([4-[2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]phenyl]carbonyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of4-[2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]benzoicacid (270 mg, 0.59 mmol, 1.00 equiv), HATU (239 mg, 0.63 mmol, 1.00equiv), DIPEA (325 mg, 2.51 mmol, 4.00 equiv), Int-A4 (118 mg, 0.63mmol, 1.00 equiv) in DMF (2 mL) was stirred for 30 min at roomtemperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN yielding the titlecompound (163.6 mg 44%) as a white solid. LCMS (ESI, m/z): 632.22[M+H]⁺, ¹H NMR (DMSO-d₆, 300 MHz) δ:12.52 (s, 1H), 8.49 (d, J=2.3 Hz,1H), 7.99 (s, 1H), 7.87 (dd, J=9.1, 2.3 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H),7.31 (t, J=7.8 Hz, 1H), 7.09-6.87 (m, 5H), 4.96 (s, 2H), 4.86 (s, 2H),4.43-4.40 (d, J=9.3 Hz, 4H), 3.73 (dr, 4H), 3.59 (dr, 4H).

Example 44:5-[5-fluoro-6-(piperidin-3-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of5-(5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of 5-bromo-6-fluoro-2,3-dihydro-1H-isoindole (6 g, 27.77mmol, 1 equiv),5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(10.8 g, 32.85 mmol, 1.183 equiv), TEA (8 g, 79.06 mmol, 2.847 equiv) inethanol (60 mL) was stirred for 2 h at 80° C. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (2/8) to afford 2.8 g (19.8%)of the title compound as a white solid. LCMS (ESI, m/z): 510.06[M+H]⁺

Step 2: Synthesis of Tert-Butyl3-[([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)methyl]piperidine-1-carboxylate

A solution of5-(5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1 g, 1.97 mmol, 1.00 equiv), Rockphos (92 mg, 0.20 mmol, 0.10 equiv),[Pd(ally)Cl]₂, Cs₂CO₃ (72 mg, 0.20 mmol, 0.10 equiv), tert-butyl3-(hydroxymethyl)piperidine-1-carboxylate (844 mg, 3.92 mmol, 2.00equiv), Cs₂CO₃ (1.28 g, 3.93 mmol, 2.00 equiv) in toluene (8 mL) wasstirred for 2 h under the atmosphere of nitrogen at 80° C. The reactionmixture was concentrated under vacuum and the residue was applied onto asilica gel column eluting with EtOAc/petroleum ether (3/7) to afford 920mg (92%) of the title compound as yellow oil. LCMS (ESI, m/z): 643.29[M+H]⁺

Step 3: Synthesis of5-[5-fluoro-6-(piperidin-3-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of tert-butyl3-[([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)methyl]piperidine-1-carboxylate(910 mg, 1.42 mmol, 1 equiv) in hydrogen chloride/dioxane (10 mL) wasstirred for 3 h at room temperature. After concentration, the residuewas purified by C18 reverse phase chromatography eluting with H₂O/CH₃CN.Then the residue was further purified by Prep-HPLC yielding the titlecompound (29.4 mg, 5.04%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ:7.98 (s, 1H), 7.28-7.23 (m, 2H), 4.90 (m, 4H), 3.90 (d, J=6.6 Hz, 2H),3.04 (d, J=11.9 Hz, 1H), 2.86 (d, J=12.2 Hz, 1H), 2.50-2.28 (m, 1H),1.92-1.6 (m, 2H), 1.59 (d, J=12.9 Hz, 1H), 1.41 (t, J=11.8 Hz, 1H),1.28-1.15 (m, 1H).

Example 45:5-[5-[(1-acetylpiperidin-3-yl)methoxy]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[5-fluoro-6-(piperidin-3-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(120 mg, 0.29 mmol, 1 equiv), TEA (88.3 mg, 0.87 mmol, 3.0 equiv), Ac₂O(44.6 mg, 0.44 mmol, 1.5 equiv) in DCM (10 mL) was stirred for 2 h atroom temperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN. Then the residuewas further purified by Prep-HPLC yielding the title compound (31.2 mg,23.6%) as white solid. LCMS (ESI, m/z): 455.42 [M+H]⁺, ¹H NMR(Methanol-d₄, 300 MHz) δ: 8.04 (s, 1H), 7.15 (d, J=10.4 Hz, 2H),5.11-4.90 (m, 4H), 4.51 (d, J=12.9 Hz, 1H), 4.11-3.87 (m, 3H), 3.26-3.21(m, 1H), 3.04-2.78 (m, 1H), 2.12-1.82 (m, 5H), 1.79-1.54 (s, 3H)

Example 46:6-(4-[[4-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrimidin-2-yl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1: Synthesis of methyl4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrimidine-2-carboxylate

A solution of5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(500 mg, 1.13 mmol, 1 equiv), methyl 4-bromopyrimidine-2-carboxylate(491 mg, 2.26 mmol, 2 equiv), Pd₂(dba)₃.CHCl₃ (117 mg, 0.11 mmol, 0.1equiv), xantphos (65.5 mg, 0.11 mmol, 0.1 equiv), Cs₂CO₃ (738 mg, 2.26mmol, 2 equiv) in toluene (5 mL) with an inert atmosphere of nitrogenwas stirred for 5 h at 85° C. The resulting solution was concentratedunder vacuum. The residue was applied onto a silica gel column elutingwith EtOAc/petroleum ether (69/31) to afford 478 mg (73.1%) of the titlecompound as a white solid. LCMS (ESI, m/z): 578.20 [M+H]⁺

Step 2: Synthesis of4-((2-(6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)pyrimidine-2-carboxylate

A solution of methyl 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrimidine-2-carboxylate(458 mg, 0.79 mmol, 1 equiv), LiOH.H₂O (166 mg, 3.97 mmol, 5 equiv) inMeOH (5 mL) and H₂O (1 mL) was stirred for 6 h at room temperature. Theresulting solution was diluted with 6 mL of water. The resultingsolution was extracted with 3×30 mL of DCM and the organic layerscombined and concentrated under vacuum. This resulted in 167 mg (37.3%)of the title compound as a yellow oil. LCMS (ESI, m/z): 564.18[M+H]⁺

Step 3: Synthesis of4-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrimidine-2-carboxylicAcid

A solution of4-((2-(6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)pyrimidine-2-carboxylate(157 mg) in HCl/dioxane (4 mL) was stirred for 7 h at room temperature.The resulting mixture was concentrated under vacuum. This resulted in141 mg of the title compound as yellow oil. LCMS (ESI, m/z): 434.10[M+H]⁺

Step 4: Synthesis of6-(4-[[4-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrimidin-2-yl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of4-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrimidine-2-carboxylicacid (131 mg, 0.30 mmol, 1 equiv), DIPEA (117.2 mg, 0.91 mmol, 3 equiv),EDC.HCl (86.9 mg, 0.45 mmol, 1.5 equiv), HOBT (61.3 mg, 0.45 mmol, 1.5equiv), Int-A4 (74.7 mg, 0.33 mmol, 1.1 equiv) in DMF (2 mL) was stirredfor 5 h at room temperature. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN.Then the residue was further purified by Prep-HPLC yielding the titlecompound (8.5 mg, 4.66%) as a white solid. LCMS (ESI, m/z): 604.20[M+H]+, ¹H NMR (400 MHz, DMSO-d6) δ: 12.61 (s, 1H), 8.61 (d, J=7 Hz,1H), 8.58 (s, 1H), 8.33 (s, 1H), 7.91 (dd, J=9.1, 2.4 Hz, 1H), 7.53-7.29(m, 4H), 6.98-6.88 (m, 2H), 6.15 (s, 1H), 5.10 (d, J=14.5 Hz, 1H), 4.86(dd, J=11.5, 4.4 Hz, 1H), 4.66 (dd, J=11.5, 4.6 Hz, 1H), 4.55 (d, J=14.9Hz, 1H), 3.80 (d, J=5.5 Hz, 2H), 3.72 (t, J=4.2 Hz, 2H), 3.63 (t, J=5.2Hz, 2H), 3.29 (m, 2H).

Example 47:N-[4-[(5-cyanopyridin-2-yl)oxy]cyclohexyl]-2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]acetamide

Step 1: Synthesis of Tert-ButylN-[4-[(5-cyanopyridin-2-yl)oxy]cyclohexyl]carbamate

To a solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (2 g, 9.29mmol, 1.00 equiv) in DMF (10 mL), sodium hydride (223 mg, 9.29 mmol,2.00 equiv) was added in at 0° C., then the resulting solution wasstirred for 10 min at room temperature, then6-chloropyridine-3-carbonitrile (1.3 g, 9.38 mmol, 1.00 equiv) was addedin, the resulting solution was stirred for another 8 h at roomtemperature, and then the resulting solution was diluted with 50 mL ofwater, extracted with 2×50 mL of EtOAc, and the organic layers combinedand washed with 1×50 mL of brine, dried over anhydrous sodium sulfateand then concentrated under vacuum and then the residue was applied ontoa silica gel column eluting with EtOAc/petroleum ether (2:3) to afford1.7 g (58%) of the title compound as a white solid. LCMS (ESI, m/z):318.18 [M+H]⁺.

Step 2: Synthesis of 6-[(4-aminocyclohexyl)oxy]pyridine-3-carbonitrile

A solution of tert-butylN-[4-[(5-cyanopyridin-2-yl)oxy]cyclohexyl]carbamate (700 mg, 2.21 mmol,1.00 equiv) in hydrogen chloride/dioxane (5 mL, 4M) was stirred for 30min at room temperature, and then the resulting solution wasconcentrated under vacuum to afford 100 mg of the title compound as acrude white solid. LCMS (ESI, m/z): 218.12 [M+H]⁺.

Step 3: Synthesis ofN-[4-[(5-cyanopyridin-2-yl)oxy]cyclohexyl]-2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]acetamide

A solution of2-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxyaceticacid (72 mg, 0.22 mmol, 1.00 equiv), EDC.HCl (86 mg, 0.55 mmol, 2.00equiv), DMAP (55 mg, 0.45 mmol, 2.00 equiv) and6-[(4-aminocyclohexyl)oxy]pyridine-3-carbonitrile (58 mg, 0.27 mmol,1.20 equiv) in DMF (4 mL) was stirred for 16 h at room temperature, andthen the resulting solution was diluted with 20 ml of H2O, extractedwith 3×20 ml of EtOAc and the organic layer was combined, washed with1×20 mL of brine and concentrated under vacuum, and then the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN.After concentration, the residue was further purified by Pre-HPLCyielding the title compound (23 mg, 20%) as a yellow solid. LCMS (ESI,m/z): 521.20[M+H]+, ¹H NMR (CD3OD, 400 MHz) δ 8.55 (dd, J=2.4, 0.8 Hz,1H), 8.27 (s, 1H), 7.97 (dd, J=8.4, 2.4 Hz, 1H), 6.88 (dd, J=8.8, 0.8Hz, 1H), 5.13-5.06 (m, 1H), 4.79-4.71 (m, 1H), 3.97 (d, J=8.8 Hz, 2H),3.82-3.71 (m, 3H), 3.42-3.37 (m, 2H), 2.32-2.17 (m, 3H), 2.06-1.92 (m,3H), 1.83-1.69 (m, 2H), 1.68-1.58 (m, 2H), 1.45-1.38 (m, 2H)

Example 48:5-[5-fluoro-6-(pyrrolidin-2-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of Tert-Butyl2-[([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)methyl]pyrrolidine-1-carboxylate

Under nitrogen, a solution of5-(5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(800 mg, 1.57 mmol, 1.00 equiv), tert-butyl2-(hydroxymethyl)pyrrolidine-1-carboxylate (952 mg, 4.73 mmol, 3.00equiv), [Pd(allyl)Cl]₂ (17 mg, 0.05 mmol, 0.03 equiv), Rockphos (37 mg,0.08 mmol, 0.05 equiv), Cs₂CO₃ (1.03 mg, 2.00 equiv) in toluene (4 mL)was stirred for 5 h at 90° C. in an oil bath. After concentration, theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (23:77) to afford 800 mg (81%) of the titlecompound as yellow oil. LCMS (ESI, m/z): 629.27 [M+H]⁺

Step 2: Synthesis of5-[5-fluoro-6-(pyrrolidin-2-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of tert-butyl2-[([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)methyl]pyrrolidine-1-carboxylate(800 mg, 1.27 mmol, 1.00 equiv) in hydrogen chloride/dioxane (30 mL) wasstirred for 1 overnight at 25° C. After concentration, the crude productwas purified by Prep-HPLC yielding the title compound (18.6 mg 4%) as awhite solid. LCMS (ESI, m/z): 399.14 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz)δ: 12.50 (s, 1H), 7.93 (s, 1H), 7.28-7.20 (m, 2H), 4.90 (s, 4H),3.88-3.85 (m, 2H), 3.37-3.33 (m, 1H), 2.83-2.78 (m, 2H), 1.87-1.80 (m,1H), 1.73-1.66 (m, 2H), 1.49-1.41 (m, 1H).

Example 49:5-[5-fluoro-6-[(1-methylpyrrolidin-2-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one;Formic Acid

A solution of5-[5-fluoro-6-(pyrrolidin-2-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(150 mg, 0.38 mmol, 1.00 equiv), CH₂O (20 mg, 0.67 mmol, 1.80 equiv),potassium hydroxide (42 mg, 0.75 mmol, 2.00 equiv), NaBH₄ (29 mg, 0.77mmol, 2.00 equiv) in methanol (20 mL) was stirred for 3 h at 25° C.After concentration, the residue was purified by Prep-HPLC yielding thetitle compound (41.6 mg 24%) as a colorless solid. LCMS (ESI, m/z):413.15 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz, ppm) δ: 12.50 (s, 1H), 7.97 (s,1H), 7.22-7.28 (m, 2H), 4.89 (s, 4H), 4.04-3.91 (m, 2H), 2.99-2.95 (m,1H), 2.67-2.62 (m, 1H), 2.38 (s, 3H), 2.23-2.19 (m, 1H), 2.00-1.92 (s,1H), 1.73-1.66 (m, 2H), 1.59-1.56 (m, 1H).

Example 50:5-[5-[(1-acetylpyrrolidin-2-yl)methoxy]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[5-fluoro-6-(pyrrolidin-2-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(100 mg, 0.25 mmol, 1.00 equiv), TEA (51 mg, 0.50 mmol, 2.00 equiv) andAc₂O (26 mg, 0.25 mmol, 1.00 equiv) in DCM (3 mL) was stirred for 1 h atroom temperature, and then the resulting solution concentrated undervacuum and then the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN, after concentration, the residuewas further purified by Pre-HPLC yielding the title compound (20 mg,18.0%) as a light yellow solid. LCMS (ESI, m/z): 441.05 [M+H]⁺. ¹HNMR(Methanol-d₄, 300 MHz) δ 8.02 (s, 1H), 7.17 (dd, J=8.1, 3.0 Hz, 1H),7.10 (s, 1H), 4.87-4.97 (d, J=4.5 Hz, 4H), 4.37 (d, J=3.3 Hz, 1H), 4.17(t, J=3.0 Hz, 1H), 4.06 (d, J=1.2 Hz, 1H), 3.68-3.53 (m, 2H), 2.27-1.92(m, 7H).

Example 51:6-[4-(3-[[(2S,4S)-4-Hydroxy-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1:5-[(2S,4S)-4-Hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of (3S,5S)-5-(hydroxymethyl)pyrrolidin-3-ol hydrochloride(653 mg, 4.25 mmol, 1.00 equiv), Int-A6 (2.1 g, 6.39 mmol, 1.50 equiv)and TEA (1.3 g, 12.85 mmol, 3.00 equiv) in ethanol (50 mL) was stirredfor 1 h at 60° C. The resulting solution was concentrated under vacuumand the residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (100:0) to afford 1.2 g (69%) of the titlecompound as a white solid. LCMS (ESI, m/z): 410.16 [M+H]⁺.

Step 2: Synthesis of methyl3-[[(2S,4S)-4-hydroxy-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate

Under nitrogen, a solution of5-[(2S,4S)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(700 mg, 1.71 mmol, 1.00 equiv), [Pd(allyl)Cl]₂ (63 mg, 0.10 equiv),Rockphos (80 mg, 0.10 equiv), Cs₂CO₃ (1.1 g) and methyl 3-bromobenzoate(731 mg, 3.40 mmol, 2.00 equiv) in toluene (25 mL) was stirred for 20 hat 80° C. The resulting mixture was concentrated under vacuum, and theresidue was diluted with 80 mL of EtOAc, washed with 3×60 mL of H₂O,dried over anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1:1) to afford 390 mg (42%) of the title compoundas a brown solid. LCMS (ESI, m/z): 544.20 [M+H]⁺.

Step 3: Synthesis of3-[[(2S,4S)-4-hydroxy-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicAcid

A solution of methyl3-[[(2S,4S)-4-hydroxy-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate(140 mg, 0.26 mmol, 1.00 equiv) and LiOH (31 mg, 1.29 mmol, 5.00 equiv)in methanol (3 mL) and water (1 mL) was stirred for 2 h at roomtemperature. The resulting solution was concentrated under vacuum andthe residue was diluted with 10 mL of H₂O, and then the pH value of thesolution was adjusted to 3 with hydrogen chloride (36.5%). The solid wascollected by filtration to afford 127 mg (93%) of the title compound asa white solid. LCMS (ESI, m/z): 530.19 [M+H]⁺.

Step 4: Synthesis of6-[4-[(3-[[(2S,4S)-4-hydroxy-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-[[(2S,4S)-4-hydroxy-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicacid (120 mg, 0.30 mmol, 1.00 equiv), HATU (87 mg, 0.23 mmol, 1.00equiv), DIPEA (59 mg, 0.46 mmol, 2.00 equiv) and Int-A4 (51 mg, 0.27mmol, 1.20 equiv) in DMF (1 mL) was stirred for 1 h at room temperature.The residue was purified by C18 reverse phase chromatography elutingwith H₂O/CH₃CN to afford 131 mg (62%) of the title compound as a whitesolid. LCMS (ESI, m/z): 700.28[M+H]⁺.

Step 5: Synthesis of6-[4-(3-[[(2S,4S)-4-hydroxy-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-(3-[[(2S,4S)-4-hydroxy-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoyl)piperazin-1-yl]pyridine-3-carbonitrile(130 g, 185.77 mmol, 1.00 equiv) in hydrogen chloride/dioxane (5 mL, 4M)was stirred for 2 h at room temperature. The resulting solution wasconcentrated under vacuum and the residue was purified by C18 reversephase chromatography eluting with 1H₂O/CH₃CN. After concentration, theresidue was further purified by Prep-HPLC yielding the title compound(18.9 mg, 18%) as a white solid. LCMS (ESI, m/z): 570.10[M+H]⁺. ¹HNMR(Methanol-d₄, 300 MHz) δ 8.45 (d, J=2.1 Hz, 1), 8.22 (s, 1H), 7.81 (dd,J=9.0, 2.4 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.06 (dt, J=8.4, 2.2 Hz,2H), 6.97 (d, J=1.5 Hz, 1H), 6.92-6.87 (m, 1H), 4.96-4.91 (m, 1H),4.37-4.21 (m, 2H), 4.18 (dd, J=10.2, 6.9 Hz, 1H), 3.92-3.51 (m, 10H),2.54 (dt, J=14.4, 7.4 Hz, 1H), 1.86 (dt, J=12.6, 8.0 Hz, 1H).

Example 52:6-[4-[(4-[[(2S,4R)-4-hydroxy-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of 1-tert-butyl 2-methyl(2S,4R)-4-[(tert-butyldimethylsilyl)oxy]pyrrolidine-1,2-dicarboxylate

To a stirred solution of 1-tert-butyl 2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.5 g, 10.19 mmol, 1.00equiv) in DCM (50 mL), imidazole (1.5 g) and TBSCl (3 g) were added. Theresulting solution was stirred for 2 h at room temperature. Theresulting solution was diluted with 300 mL of DCM. The resulting mixturewas washed with 50 mL of 1M hydrogen chloride and 50 mL of brine. Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder vacuum. This resulted in 3.5 g (crude) of the title compound as asolid. LCMS (ESI, m/z): 360.22 [M+H]⁺.

Step 2: Synthesis of Tert-Butyl(2S,4R)-4-[(tert-butyldimethylsilyl)oxy]-2-(hydroxymethyl)pyrrolidine-1-carboxylate

To a stirred solution of 1-tert-butyl 2-methyl(2S,4R)-4-[(tert-butyldimethylsilyl)oxy]pyrrolidine-1,2-dicarboxylate(3.5 g, 9.73 mmol, 1.00 equiv) in THF (30 mL), LiBH₄ (20 mL) was addeddropwise at 0° C. The resulting solution was stirred overnight at roomtemperature. The reaction was then quenched by the addition of 10 mL ofmethanol. The resulting mixture was concentrated under vacuum. Theresulting solution was diluted with 250 mL of EtOAc. The resultingmixture was washed with 2×50 mL of water and 1×50 mL of brine. Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was applied onto a silica gel column withEtOAc/petroleum ether (1:3). This resulted in 3 g (93%) of the titlecompound as an oil. LCMS (ESI, m/z): 332.23 [M+H]⁺.

Step 3: Synthesis of Tert-Butyl(2S,4R)-4-[(tert-butyldimethylsilyl)oxy]-2-[3-(methoxycarbonyl)phenoxy-ethyl]pyrrolidine-1-carboxylate

A solution of tert-butyl(2S,4R)-4-[(tert-butyldimethylsilyl)oxy]-2-(hydroxymethyl)pyrrolidine-1-carboxylate(2 g, 6.03 mmol, 1.00 equiv), methyl 3-bromobenzoate (2.8 g, 13.02 mmol,2.16 equiv), Rockphos (300 mg), Pd(allyl)Cl₂ (240 mg) and Cs₂CO₃ (5 g,15.35 mmol, 2.54 equiv) in toluene (30 mL) was stirred overnight at 90°C. under an inert atmosphere of nitrogen. The solids were filtered out.The resulting solution was diluted with 250 mL of EtOAc. The resultingmixture was washed with 2×50 mL of water and 50 mL of brine. The organiclayer was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column withEtOAc/petroleum ether (1:9).

This resulted in 1.7 g (crude) of the title compound as oil. LCMS (ESI,m/z): 466.26 [M+H]⁺.

Step 4: Synthesis of methyl3-[[(2S,4R)-4-hydroxypyrrolidin-2-yl]methoxy]benzoate Hydrochloride

A solution of tert-butyl(2S,4R)-4-[(tert-butyldimethylsilyl)oxy]-2-[3-(methoxycarbonyl)phenoxymethyl]-pyrrolidine-1-carboxylate(1.6 g, 3.44 mmol, 1.00 equiv) in hydrogen chloride/dioxane (15 mL) wasstirred for 2 h at room temperature. The solids were collected byfiltration. This resulted in 660 mg (67%) of the title compound as asolid. LCMS (ESI, m/z): 252.12 [M+H]⁺.

Step 5: Synthesis of methyl3-[[(2S,4R)-4-hydroxy-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate

A solution of methyl3-[[(2S,4R)-4-hydroxypyrrolidin-2-yl]methoxy]benzoate hydrochloride (660mg, 2.29 mmol, 1.00 equiv), Int-A6 (750 mg, 2.28 mmol, 0.99 equiv) andTEA (3 mL) in ethanol (20 mL) was stirred for 1 h at 60° C. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with EtOAc/petroleum ether (1:1). This resultedin 550 mg (44%) of the title compound as an oil. LCMS (ESI, m/z): 544.21[M+H]⁺.

Step 6: Synthesis of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicAcid

To a stirred solution of methyl3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate(550 mg, 1.04 mmol, 1.00 equiv) in THF (15 mL) and water (5 mL), LiOH(150 mg, 6.26 mmol, 6.01 equiv) was added. The resulting solution wasstirred overnight at room temperature. The pH value of the solution wasadjusted to 1 with hydrogen chloride (1 M). The resulting solution wasextracted with 250 mL of EtOAc and washed with 50 mL of brine. Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder vacuum. This resulted in 550 mg (crude) of the title compound as asolid. LCMS (ESI, m/z): 530.19 [M+H]⁺.

Step 7: Synthesis of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicAcid

A solution of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydrop-yridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicacid (550 mg, 1.07 mmol, 1.00 equiv) in hydrogen chloride/dioxane (10mL) was stirred overnight at room temperature. The resulting mixture wasconcentrated under vacuum. This resulted in 400 mg (crude) of the titlecompound as oil. LCMS (ESI, m/z): 400.11 [M+H]⁺.

Step 8: Synthesis of6-[4-[(4-[[(2S,4R)-4-hydroxy-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

To a stirred solution of4-[[(2S,4R)-4-hydroxy-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexane-1-carboxylicacid (400 mg, 0.99 mmol, 1.00 equiv) in DMF (10 mL), Int-A4 (188 mg,1.00 mmol, 1.01 equiv), DIPEA (1 mL) and HATU (500 mg, 1.31 mmol, 1.33equiv) were added. The resulting solution was stirred for 2 h at roomtemperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN. Then the residuewas further purified by Prep-HPLC yielding the title compound (88.8 mg,16%) as a white solid. LCMS (ESI, m/z): 570.15 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 12.46 (s, 1H), 8.49 (d, J=2.3 Hz, 1H), 8.20 (s, 1H), 7.87(dd, J=9.1, 2.4 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H), 7.03-6.84 (m, 4H), 5.02(d, J=3.0 Hz, 1H), 4.98-4.87 (m, 1H), 4.36-4.24 (m, 1H), 4.16 (dd,J=10.4, 3.8 Hz, 1H), 4.02 (dd, J=10.4, 5.9 Hz, 1H), 3.89-3.51 (m, 8H),3.41-3.38 (m, 1H), 3.10 (d, J=11.6 Hz, 1H), 2.16-2.02 (m, 1H), 2.02-1.88(m, 1H).

Example 53:5-(5-fluoro-6-(pyrrolidin-3-yloxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one

Step 1: Synthesis of Tert-Butyl3-([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)pyrrolidine-1-carboxylate

A solution of5-(5-fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(400 mg, 0.90 mmol, 1.00 equiv), potassium carbonate (248 mg, 1.79 mmol,2.00 equiv), and tert-butyl 3-bromopyrrolidine-1-carboxylate (447.6 mg,1.79 mmol, 1.99 equiv) in DMF (10 mL, 2.00 equiv) was stirred overnightat 80° C. The reaction was quenched by the addition of 20 mL of water.The resulting solution was extracted with 3×10 mL of EtOAc and theorganic layers combined and concentrated under vacuum. The residue wasapplied onto a silica gel column with EtOAc/petroleum ether (1/5). Thisresulted in 382 mg (69%) of the title compound as a yellow oil. LCMS(ESI, m/z): 615.25 [M+H]⁺.

Step 2: Synthesis of5-[5-fluoro-6-(pyrrolidin-3-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneHydrochloride

A solution of tert-butyl3-([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)pyrrolidine-1-carboxylate(382 mg, 0.62 mmol, 1.00 equiv) in HCl in dioxane (4 M) (10 mL) wasstirred overnight at room temperature. The resulting mixture wasconcentrated under vacuum. After concentration, the residue was purifiedby C18 reverse phase chromatography eluting with H₂O/CH₃CN yielding thetitle compound (32 mg, 19%) as a white solid. LCMS (ESI, m/z): 385.15[M+H]⁺, ¹H NMR (Methanol-d₄, 300 MHz) δ: 8.04 (s, 1H), 7.15 (dd, J=9.2,6.3 Hz, 2H), 5.05-4.99 (m, 5H), 3.22-3.07 (m, 3H), 2.99-2.97 (m, 1H),2.23-2.09 (m, 2H).

Example 54:5-(5-(1-acetylpyrrolidin-3-yloxy)-6-fluoroisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of5-[5-fluoro-6-(pyrrolidin-3-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(135 mg, 0.35 mmol, 1.00 equiv), Ac₂O (43.04 mg, 0.42 mmol, 1.20 equiv),and TEA (106.66 mg, 1.05 mmol, 3.00 equiv) in DCM (10 mL) was stirredfor 8.5 h at room temperature. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CNyielding the title compound (63.2 mg, 42%) as a white solid. LCMS (ESI,m/z): 427.20 [M+H]⁺, ¹HNMR (Methanol-d₄, 300 MHz) δ: 8.05 (s, 1H),7.24-7.13 (m, 2H), 5.10 (d, J=14.4 Hz, 1H), 4.91 (d, J=23.4 Hz, 4H),3.92-3.65 (m, 3H), 3.68-3.45 (m, 1H), 2.37-2.23 (m, 2H), 2.10 (d, J=12.4Hz, 3H).

Example 55:5-[5-fluoro-6-[(1-methylpyrrolidin-3-yl)oxy]-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[5-fluoro-6-(pyrrolidin-3-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-onehydrochloride (260 mg, 0.62 mmol, 1.00 equiv), paraformaldehyde (33.3mg, 1.11 mmol, 1.80 equiv), and potassium hydroxide (69.2 mg, 1.23 mmol,2.00 equiv) in methanol (10 mL) was stirred for 3 h at room temperature.NaBH₄ (46.9 mg, 1.24 mmol, 2.00 equiv) was added to the resultingsolution. The resulting solution was stirred for an additional 0.5 h atroom temperature. The resulting mixture was concentrated under vacuum.The crude product was purified by Prep-HPLC yielding the title compound(20.2 mg, 8%) as a white solid. LCMS (ESI, m/z): 399.10 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d6) δ 12.54 (s, 1H), 7.96 (s, 1H), 7.27 (d, J=11.0 Hz,1H), 7.14 (d, J=7.9 Hz, 1H), 4.90 (s, 5H), 2.77 (dd, J=10.5, 5.9 Hz,1H), 2.65 (ddd, J=18.8, 9.4, 3.2 Hz, 2H), 2.40-2.25 (m, 2H), 2.26 (s,3H), 1.86-1.72 (m, 1H).

Example 56 Isomer A:6-(4-[[(3S,5S)-5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]piperidin-3-yl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 56 Isomer B:6-(4-[[(3R,5R)-5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]piperidin-3-yl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1: Synthesis of methyl5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridine-3-carboxylate

A solution of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1 g, 2.54 mmol, 1.00 equiv), [Pd(allyl)Cl]₂ (93 mg, 0.10 equiv),Rockphos (119.2 mg, 0.10 equiv), Cs₂CO₃ (2.48 g, 7.61 mmol, 3.00 equiv),and methyl 5-bromopyridine-3-carboxylate (656 mg, 3.04 mmol, 1.20 equiv)in toluene (20 mL) was stirred for 15 h at 80° C. The resulting mixturewas concentrated under vacuum and the residue was applied onto a silicagel column eluting with EtOAc/petroleum ether (1:1) to afford 350 mg(26%) of the title compound as brown oil. LCMS (ESI, m/z): 529.21[M+H]⁺.

Step 2: Synthesis of methyl5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]piperidine-3-carboxylate

A solution of methyl5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridine-3-carboxylate(1 g, 1.89 mmol, 1.00 equiv), PtO₂ (1 g), acetic acid (4 mL) in methanol(25 mL) under hydrogen atmosphere was stirred for 8 h at roomtemperature. The solids were filtered out. The resulting solution wasconcentrated under vacuum to afford 1 g crude of the title compound aswhite oil. LCMS (ESI, m/z): 535.26 [M+H]⁺.

Step 3: Synthesis of 1-tert-butyl 3-methyl5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]piperidine-1,3-dicarboxylate

A solution of methyl5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]piperidine-3-carboxylate(614 mg, 1.15 mmol, 1.00 equiv), (Boc)₂O (250.6 mg, 1.15 mmol, 1.00equiv), and 4-dimethylaminopyridine (28.06 mg, 0.23 mmol, 0.20 equiv) inTHF (20 mL) was stirred for 1 h at room temperature. Afterconcentration, the residue was applied onto a silica gel column elutingwith EtOAc/petroleum ether (30:70) to afford 370 mg (51%) of the titlecompound as a white solid. LCMS (ESI, m/z): 635.31[M+H]⁺.

Step 4: Synthesis of1-[(tert-butoxy)carbonyl]-5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]piperidine-3-carboxylicAcid

A solution of 1-tert-butyl 3-methyl5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]piperidine-1,3-dicarboxylate(370 mg, 0.58 mmol, 1.00 equiv), LiOH (70 mg, 2.92 mmol, 5.00 equiv),water (2 mL) in methanol (10 mL) was stirred for 2 h at roomtemperature. The resulting mixture was concentrated under vacuum toafford 344 mg crude of the title compound as a yellow solid. LCMS (ESI,m/z): 621.30 [M+H]⁺.

Step 5: Synthesis of Tert-Butyl3-[[4-(5-cyanopyridin-2-yl)piperazin-1-yl]carbonyl]-5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]piperidine-1-carboxylate

A solution of1-[(tert-butoxy)carbonyl]-5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]piperidine-3-carboxylicacid (286 mg, 0.46 mmol, 1.00 equiv), HATU (262.2 mg, 0.69 mmol, 1.50equiv), DIPEA (178 mg, 1.38 mmol, 3.00 equiv), Int-A4 (86.7 mg, 0.46mmol, 1.00 equiv) in DMF (5 mL) was stirred for 3 h at room temperature.The resulting solution was quenched with H2O. The solution was extractedwith EtOAc (3×50 mL) and the organic layers combined. The solution wasdried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (40:60) to afford 450 mg (crude) of the titlecompound as brown oil. LCMS (ESI, m/z): 791.39 [M+H]⁺.

Step 6: Synthesis of6-(4-[[(3S,5S)-5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]piperidin-3-yl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrileand6-(4-[[(3R,5R)-5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]piperidin-3-yl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of tert-butyl3-[[4-(5-cyanopyridin-2-yl)piperazin-1-yl]carbonyl]-5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]piperidine-1-carboxylate(450 mg, 0.57 mmol, 1.00 equiv) in hydrogen chloride-dioxane (15 mL) wasstirred for 2 h at room temperature. After concentration, the residuewas purified by C18 reverse phase chromatography eluting with H₂O/CH₃CN.The residue was further purified by Prep-HPLC and Chiral-Prep-HPLC min(CHIRALPAK IE-3, 0.46*10 cm; 3 um, MtBE (0.1% DEA):EtOH=50:50, 1.0mL/min) yielding the title compounds as white solids. The assignment ofExample 56 Isomer A and Isomer B was arbitrarily assigned with assumedstructures as drawn and two isomers were isolated during chiralprep-HPLC.

Example 56 Isomer A

7.8 mg, 2%, LCMS (ESI, m/z): 561.10 [M+H]+, ¹H NMR (400 MHz,Methanol-d₄) δ 8.45 (dd, J=2.4, 0.8 Hz, 1H), 8.14 (s, 1H), 7.79 (dd,J=9.1, 2.4 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 4.58 (s, 1H), 3.90-3.80 (m,2H), 3.79-3.49 (m, 8H), 3.47 (dd, J=10.0, 7.1 Hz, 1H), 3.43-3.34 (m,2H), 3.09 (dd, J=12.3, 4.1 Hz, 1H), 2.93-2.88 (m, 2H), 2.65-2.62 (m,1H), 2.30-2.13 (m, 3H), 2.01 (q, J=11.3, 6.0 Hz, 1H), 1.87-1.73 (m, 2H),1.73-1.68 (m, 1H). tR=3.570.

Example 56 Isomer B

2%, LCMS (ESI, m/z): 561.10 [M+H]+, (400 MHz, Methanol-d4) δ 8.45 (dd,J=2.4, 0.7 Hz, 1H), 8.14 (s, 1H), 7.79 (dd, J=9.0, 2.3 Hz, 1H), 6.90(dd, J=9.1, 0.9 Hz, 1H), 4.60 (s, 1H), 3.78 (d, J=5.7 Hz, 3H), 3.79-3.71(m, 2H), 3.69 (d, J=4.7 Hz, 5H), 3.46 (dd, J=10.1, 7.4 Hz, 1H),3.43-3.34 (m, 2H), 3.18 (d, J=11.8 Hz, 1H), 3.04-2.74 (m, 2H), 2.63 (dd,J=12.5, 10.1 Hz, 1H), 2.40-2.15 (m, 2H), 2.01 (t, J=9.5 Hz, 2H), 1.74(tt, J=12.0, 7.0 Hz, 1H), 1.45 (q, J=11.2 Hz, 1H).

Example 57 Isomer A:6-[4-[(1S,3S)-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexanecarbonyl]piperazin-1-yl]pyridine-3-carbonitrileand Example 57 Isomer B:6-[4-[(1R,3R)-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexanecarbonyl]piperazin-1-yl]pyridine-3-carbonitrileand Example 57 Isomer C:6-[4-[(1S,3R)-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexanecarbonyl]piperazin-1-yl]pyridine-3-carbonitrileand Example 57 Isomer D:6-[4-[(1R,3S)-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexanecarbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl(2S)-2-[3-(methoxycarbonyl)phenoxymethyl]pyrrolidine-1-carboxylate

A solution of tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate(1 g, 4.97 mmol, 1.00 equiv), methyl 3-hydroxybenzoate (1.14 g, 7.49mmol, 1.50 equiv), PPh₃ (1.97 g, 7.51 mmol, 1.50 equiv), and DEAD (1.3g, 7.46 mmol, 1.50 equiv) in THF (20 mL) was stirred for 16 h at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (5:95) to afford 960 mg (58%) of the titlecompound as white oil. LCMS (ESI, m/z): 336.18 [M+H]⁺.

Step 2: Synthesis of Tert-Butyl(2S)-2-([[3-(methoxycarbonyl)cyclohexyl]oxy]methyl)pyrrolidine-1-carboxylate

A solution of tert-butyl(2S)-2-[3-(methoxycarbonyl)phenoxymethyl]pyrrolidine-1-carboxylate (1 g,2.98 mmol, 1.00 equiv), Rh/Al₂O₃ (2 g), acetic acid (3 mL) in methanol(20 mL) was stirred for 16 h at room temperature under an atmosphere ofhydrogen. The solids were filtered out. The resulting solution wasconcentrated under vacuum to afford 1.02 g crude of the title compoundas a yellow oil. LCMS (ESI, m/z): 342.23 [M+H]⁺.

Step 3: Synthesis of methyl3-[(2S)-pyrrolidin-2-ylmethoxy]cyclohexane-1-carboxylate

A solution of tert-butyl(2S)-2-([[3-(methoxycarbonyl)cyclohexyl]oxy]methyl)pyrrolidine-1-carboxylate(1.02 g, 2.99 mmol, 1.00 equiv) in hydrogen chloride/dioxane (15 mL) wasstirred for 1 h at room temperature. The resulting mixture wasconcentrated under vacuum to afford 723 mg crude of the title compoundas a white solid. LCMS (ESI, m/z): 242.18[M+H]⁺.

Step 4: Synthesis of methyl3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexane-1-carboxylate

A solution of Int-A6 (1 g, 3.04 mmol, 1.00 equiv), methyl3-[(2S)-pyrrolidin-2-ylmethoxy]cyclohexane-1-carboxylate (723 mg, 3.00mmol, 1.00 equiv), TEA (900 mg, 8.89 mmol, 3.00 equiv) in ethanol (15mL) was stirred for 1 h at 80° C. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withEtOAc/petroleum ether (1:4) to afford 1.2 g (74%) of the title compoundas a colorless oil. LCMS (ESI, m/z): 534.26[M+H]⁺.

Step 5: Synthesis of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexane-1-carboxylicAcid

A solution of methyl3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexane-1-carboxylate(1.3 g, 2.44 mmol, 1.00 equiv), LiOH (180 mg, 7.52 mmol, 3.09 equiv),water (5 mL) in methanol (25 mL) was stirred for 2 h at roomtemperature. The resulting mixture was concentrated under vacuum toafford 1.2 g crude of the title compound as a white solid. LCMS (ESI,m/z): 520.24[M+H]⁺.

Step 6: Synthesis of6-[4-[(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexane-1-carboxylicacid (400 mg, 0.77 mmol, 1.10 equiv), HATU (346 mg, 0.91 mmol, 1.30equiv), DIPEA (180 mg, 1.39 mmol, 2.00 equiv), Int-A4 (132 mg, 0.70mmol, 1.00 equiv) in DMF (3 mL) was stirred for 2 h at room temperature.The resulting solution was quenched with 40 ml water. The solution wasextracted with EtOAc (3×50 mL) and the organic layers were combined. Thesolution was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1:1) to afford 500 mg (94%) of the title compoundas a white solid. LCMS (ESI, m/z): 690.34[M+H]⁺.

Step 7: Synthesis of6-[4-[(1S,3S)-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexanecarbonyl]piperazin-1-yl]pyridine-3-carbonitrile,6-[4-[(1R,3R)-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexanecarbonyl]piperazin-1-yl]pyridine-3-carbonitrile,6-[4-[(1S,3R)-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexanecarbonyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(1R,3S)-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexanecarbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexanecarbonyl)piperazin-1-yl]pyridine-3-carbonitrile(500 mg, 0.72 mmol, 1 equiv) in HCl/dioxane (15 mL) was stirred for 2 hat room temperature. After concentration, the residue was purified byC18 reverse phase chromatography eluting with H₂O/CH₃CN. The residue wasfurther purified by Prep-HPLC and Chiral-Prep-HPLC (Repaired IC, 0.46*10cm; 5 um, (Hex:DCM=1:1)(0.1% DEA):EtOH=70:30, 1.0 mL/min) yielding(after arbitrary assignment of the stereochemistry) the title compoundsas white solids.

Example 57 Isomer A

28.4 mg, 7.12%, LCMS (ESI, m/z): 560.15 [M+H]⁺, ¹H NMR (300 MHz,Methanol-d4) δ 8.44 (dd, J=2.4, 0.7 Hz, 1H), 8.16 (s, 1H), 7.78 (dd,J=9.1, 2.4 Hz, 1H), 6.90 (dd, J=9.1, 0.8 Hz, 1H), 4.59 (q, J=7.6, 3.6Hz, 1H), 3.81-3.68 (m, 10H), 3.47-3.35 (m, 2H), 2.72 (t, J=11.7 Hz, 1H),2.23 (s, 1H), 2.13-1.96 (m, 2H), 1.92-1.60 (m, 5H), 1.56-0.85 (m, 5H).tR=3.718 min.

Example 57 Isomer B

31.2 mg, 7.69%, LCMS (ESI, m/z): 560.15 [M+H]⁺, ¹H NMR (300 MHz,Methanol-d4) δ 8.45 (dd, J=2.4, 0.8 Hz, 1H), 8.15 (s, 1H), 7.78 (dd,J=9.1, 2.4 Hz, 1H), 6.89 (dd, J=9.1, 0.8 Hz, 1H), 4.58 (q, J=7.4, 3.5Hz, 1H), 3.84-3.66 (m, 10H), 3.47 (dd, J=10.0, 7.2 Hz, 1H), 3.36 (s,1H), 2.75 (t, J=11.6 Hz, 1H), 2.27-2.18 (m, 1H), 2.09-1.92 (m, 3H),1.88-1.66 (m, 4H), 1.48-1.24 (m, 4H), 1.08 (t, J=11.5 Hz, 1H). tR=4.396min.

Example 57 Isomer C

6.2 mg, 1.53%, LCMS (ESI, m/z): 560.15 [M+H]⁺, ¹H NMR (300 MHz,Methanol-d4) δ 8.46 (d, J=2.3 Hz, 1H), 8.35 (s, 1H), 7.80 (dd, J=9.0,2.4 Hz, 1H), 6.93 (d, J=9.1 Hz, 1H), 4.75 (s, 1H), 3.91-3.78 (m, 7H),3.77-3.58 (m, 3H), 3.57-3.43 (m, 3H), 2.79 (t, J=11.2 Hz, 1H), 2.28 (d,J=10.7 Hz, 1H), 2.06-1.59 (m, 7H), 1.58-1.21 (m, 4H). tR=3.555 min.

Example 57 Isomer D

4.7 mg, 1.16%, LCMS (ESI, m/z): 560.15 [M+H]⁺, ¹H NMR (300 MHz,Methanol-d4) δ 8.46 (d, J=2.4 Hz, 1H), 8.34 (s, 1H), 7.80 (dd, J=9.0,2.4 Hz, 1H), 6.92 (d, J=9.0 Hz, 1H), 4.92 (s, 1H), 3.93-3.65 (m, 9H),3.64-3.55 (m, 2H), 3.54-3.43 (m, 2H), 2.86 (t, J=11.7 Hz, 1H), 2.27 (dd,J=11.9, 6.9 Hz, 1H), 2.09-1.91 (m, 2H), 1.84-1.62 (m, 7H), 1.61-1.43 (m,2H). tR=4.035 min.

Example 58:5-[5-fluoro-6-(piperidin-3-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of Tert-Butyl3-(methanesulfonyloxy)piperidine-1-carboxylate

A solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (950 mg, 4.72mmol, 1.00 equiv), TEA (955 mg, 9.44 mmol, 2.00 equiv), methanesulfonylmethanesulfonate (1.64 g, 9.41 mmol, 2.00 equiv) in DCM (10 mL) wasstirred overnight at room temperature. The resulting solution wasdiluted with 50 mL of DCM. The resulting mixture was washed with 3×30 mLof sodium bicarbonate/H₂O. The resulting mixture was concentrated undervacuum. This resulted in 826 mg (63%) of the title compound as a solid.LCMS (ESI, m/z): 280.10 [M+H]⁺.

Step 2: Synthesis of Tert-Butyl3-([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate

A solution of5-(5-fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(445 mg, 1.00 mmol, 1.00 equiv), Cs₂CO₃ (652 mg, 2.00 mmol, 2.00 equiv),tert-butyl 3-(methanesulfonyloxy)piperidine-1-carboxylate (840 mg, 3.01mmol, 3.00 equiv) in DMF (10 mL) was stirred for 2 days at 80° C. Thereaction was quenched by the addition of 20 mL of water. The resultingsolution was extracted with 3×10 mL of EtOAc and the organic layerscombined and concentrated under vacuum. The residue was applied onto asilica gel column with EtOAc/petroleum ether (1/4). The collectedfractions were combined and concentrated under vacuum. This resulted in208 mg (33%) of the title compound as yellow crude oil. LCMS (ESI, m/z):629.27 [M+H]⁺.

Step 3:5-[5-fluoro-6-(piperidin-3-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of tert-butyl3-([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate(208 mg, 0.33 mmol, 1.00 equiv) in HCl/dioxane (4 M) (10 mL) was stirredovernight at room temperature. The resulting mixture was concentratedunder vacuum. The crude product was purified by Prep-HPLC yielding thetitle compound (23.1 mg, 18%) as a white solid. LCMS (ESI, m/z): 399.20[M+H]⁺. ¹H NMR (300 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.2-7.15 (m, 2H), 5.01(s, 4H), 4.42 (s, 1H), 3.21 (d, J=12.7 Hz, 1H), 2.99-2.89 (m, 3H),2.05-1.90 (m, 2H), 1.89-1.80 (m, 1H), 1.64-1.58 (m, 1H).

Example 59:4-Chloro-5-(5-fluoro-2,3-dihydro-1H-isoindol-2-yl)-2,3-dihydropyridazin-3-one

A solution of 4,5-dichloro-2,3-dihydropyridazin-3-one (211 mg, 1.28mmol, 1.00 equiv), 5-fluoro-2,3-dihydro-1H-isoindole hydrochloride (200mg, 1.15 mmol, 1.00 equiv), and TEA (251 mg, 2.48 mmol, 2.00 equiv) wasstirred for 6 h at 80° C. The solids were collected by filtration,washed with 2×5 mL of MeOH and 2×5 mL of H₂O to afford 139.9 mg (41%) oftitle compound as a white solid. LCMS: [M+H]⁺ 266.05, ¹H NMR (400 MHz,DMSO-d₆) δ 12.70 (s, 1H), 7.80 (s, 1H), 7.41 (dd, J=8.4, 5.1 Hz, 1H),7.24 (dd, J=9.0, 2.4 Hz, 1H), 7.21-7.11 (m, 1H), 5.19 (s, 2H), 5.13 (s,2H).

Example 60:4-Chloro-5-(4-fluoro-2,3-dihydro-1H-isoindol-2-yl)-2,3-dihydropyridazin-3-one

A solution of 4,5-dichloro-2,3-dihydropyridazin-3-one (212 mg, 1.29mmol, 1.00 equiv), 4-fluoro-2,3-dihydro-1H-isoindole hydrochloride (200mg, 1.15 mmol, 1.00 equiv), and TEA (249 mg, 2.46 mmol, 2.00 equiv) inEtOH (4 mL) was stirred for 6 h at 80° C. The solids were collected byfiltration, and washed with 2×10 mL of MeOH and 2×10 mL of H₂O to afford121.3 mg (36%) of title compound as a white solid. LCMS: [M+H]⁺ 266.05,¹H NMR (400 MHz, DMSO-d₆) δ12.72 (s, 1H), 7.87 (s, 1H), 7.40 (td, J=7.9,5.2 Hz, 1H), 7.24 (d, J=7.5 Hz, 1H), 7.16 (dd, J=9.5, 8.2 Hz, 1H), 5.23(s, 4H).

Example 61:6-(4-[[2-fluoro-5-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridin-3-yl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1: Synthesis of methyl2-fluoro-5-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-3-carboxylate

Under nitrogen, a solution of5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1 g, 2.26 mmol, 1.00 equiv), methyl5-bromo-2-fluoropyridine-3-carboxylate (2 g, 8.55 mmol, 4.00 equiv),[Pd(allyl)Cl]₂ (125 mg, 0.34 mmol, 0.15 equiv), Rockphos (160 mg, 0.34mmol, 0.15 equiv), Cs₂CO₃ (1.85 g, 5.68 mmol, 2.51 equiv) in toluene (20mL) was stirred overnight at 80° C. in an oil bath. After concentration,the residue was purified by C18 reverse phase chromatography elutingwith H₂O/CH₃CN to afford 300 mg (22%) of the title compound as a yellowsolid. LCMS (ESI, m/z): 595.19 [M+H]⁺.

Step 2: Synthesis of2-fluoro-5-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-3-carboxylicAcid

A solution of methyl2-fluoro-5-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-3-carboxylate(300 mg, 0.50 mmol, 1.00 equiv), LiOH (40 mg, 1.67 mmol, 1.70 equiv) inwater (1 mL) and methanol (40 mL) was stirred overnight at 25° C. The pHvalue of the solution was adjusted to 5-6 with hydrogen chloride (6 M).After concentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford 290 mg (99%) of thetitle compound as red oil. LCMS (ESI, m/z): 581.18 [M+H]⁺

Step 3: Synthesis of2-fluoro-5-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-3-carboxylicAcid

A solution of 2-fluoro-5-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-3-carboxylicacid (290 mg, 0.50 mmol, 1.00 equiv) and hydrogen chloride/dioxane (10mL) in dioxane (2 mL) was stirred overnight at 25° C. The resultingmixture was concentrated under vacuum to afford 200 mg (89%) of thetitle compound as a crude red oil. LCMS (ESI, m/z): 451.10 [M+H]⁺.

Step 4: Synthesis of6-(4-[[2-fluoro-5-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridin-3-yl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of2-fluoro-5-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-3-carboxylicacid (130 mg, 0.29 mmol, 1.00 equiv), HATU (112 mg, 0.29 mmol, 1.02equiv), DIPEA (112 mg, 0.87 mmol, 3.00 equiv), and Int-A4 (55 mg, 0.29mmol, 1.00 equiv) in DMF (2 mL) was stirred for 1 h at 25° C. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN yielding the title compound (20.4mg 11%) as an off-white solid. LCMS (ESI, m/z): 621.19 [M+H]⁺, 1H NMR(Methanol-d₄, 400 MHz) δ: 8.45-8.44 (d, J=2.3 Hz, 1H), 8.39 (s, 1H),7.93-7.91 (dd, J=3.1, 1.7 Hz, 1H), 7.79-7.77 (dd, J=9.1, 2.4 Hz, 1H),7.57-7.51 (m, 2H), 7.42-7.37 (m, 3H), 6.92-6.89 (d, J=9.0 Hz, 1H), 6.21(s, 1H), 5.34-5.30 (d, J=14.8 Hz, 1H), 4.69-4.67 (d, J=14.6 Hz, 1H),4.59-4.56 (dd, J=10.2, 3.6 Hz, 1H), 4.40-4.32 (dd, J=10.1, 6.3 Hz, 1H),3.87 (dr, 4H), 3.76-3.73 (m, 2H), 3.47-3.44 (d, J=5.6 Hz, 2H).

Example 62:2-(4-[[2-fluoro-5-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridin-3-yl]carbonyl]piperazin-1-yl)pyrimidine-5-carbonitrile

A solution of2-fluoro-5-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-3-carboxylicacid (130 mg, 0.29 mmol, 1.00 equiv), DIPEA (200 mg, 1.55 mmol, 6.00equiv), HATU (180 mg, 0.47 mmol, 2.00 equiv), and Int-A1 (100 mg, 0.44mmol, 1.00 equiv) in DMF (2 mL) was stirred for 1 h at 25° C. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN and further purified by Prep-HPLCto yield the title compound (25.1 mg 14%) as a white solid. LCMS (ESI,m/z): 622.19 [M+H]⁺, ¹H NMR (Methanol-d₄, 400 MHz) δ: 8.65 (m, 2H), 8.37(s, 1H), 7.90-7.89 (dd, J=3.1, 1.7 Hz, 1H), 7.55-7.49 (m, 2H), 7.40-7.34(m, 3H), 6.19 (s, 1H), 5.32-5.28 (d, J=14.4 Hz, 1H), 4.69-4.53 (m, 2H),4.37-4.30 (m, 1H), 4.06-4.03 (t, J=5.5 Hz, 2H), 3.95-3.92 (t, J=5.3 Hz,2H), 3.83-3.81 (t, J=5.4 Hz, 2H), 3.48-3.41 (t, J=5.2 Hz, 2H).

Example 63:3-[(5-cyanopyridin-2-yl)amino]-N-[5-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridin-3-yl]propanamide

Step 1: Synthesis of5-(1-[[(5-nitropyridin-3-yl)oxy]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

Under nitrogen, a solution of5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(500 mg, 1.13 mmol, 1.00 equiv), (Pd(allyl)C₁)₂ (41 mg), Rockphos (53mg), Cs₂CO₃ (1.1 g, 3.38 mmol, 2.98 equiv) and 3-bromo-5-nitropyridine(465 mg, 2.29 mmol, 2.02 equiv) in toluene (10 mL) was stirred for 16 hat 80° C. The resulting solution was concentrated under vacuum and theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (2:3) to afford 500 mg (78%) of the title compoundas a brown solid. LCMS (ESI, m/z): 564.18[M+H]⁺.

Step 2: Synthesis of5-(1-[[(5-aminopyridin-3-yl)oxy]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-(1-[[(5-nitropyridin-3-yl)oxy]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(500 mg, 0.89 mmol, 1.00 equiv) and Fe (149 mg, 3.00 equiv) in aceticacid (4 mL) was stirred for 4 h at 60° C. The solid was filtered out andthe resulting solution was concentrated under vacuum, and the residuewas applied onto a silica gel column eluting with EtOAc/petroleum ether(3:1) to afford 415 mg (88%) of the title compound as a light yellowsolid. LCMS (ESI, m/z): 534.21[M+H]⁺.

Step 3: Synthesis of3-[(5-cyanopyridin-2-yl)amino]-N-[5-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridin-3-yl]propanamide

A solution of5-(1-[[(5-aminopyridin-3-yl)oxy]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(300 mg, 0.56 mmol, 1.00 equiv), EDC.HCl (325 mg, 1.70 mmol, 3.00equiv), 4-dimethylaminopyridine (122 mg, 3.00 equiv) and3-[(5-cyanopyridin-2-yl)amino]propanoic acid (215 mg, 1.12 mmol, 2.00equiv) in DMF (2.5 mL) was stirred for 5 h at 60° C. The resultingsolution was diluted with 10 mL of H₂O, extracted with 3×15 mL of EtOAc,dried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (2:3) to afford 100 mg (25%) of the title compoundas a light yellow solid. LCMS (ESI, m/z): 707.27[M+H]⁺

Step 4: Synthesis of3-[(5-cyanopyridin-2-yl)amino]-N-[5-([2-[6-oxo-5-((trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridin-3-yl]propanamide

A solution of3-[(5-cyanopyridin-2-yl)amino]-N-[5-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridin-3-yl]propanamide(90 mg, 0.13 mmol, 1.00 equiv) and TFA (0.5 mL) in DCM (2 mL) wasstirred for 3 h at room temperature. The resulting solution wasconcentrated under vacuum and then the residue was purified by Prep-HPLCyielding the title compound (40 mg, 54%) as a white solid. LCMS (ESI,m/z): 577.15[M+H]⁺. ¹HNMR (Methanol-d₄, 300 MHz) δ 8.40 (s, 1H), 8.32(dd, J=2.1, 0.8 Hz, 1H), 8.21 (d, J=2.1 Hz, 1H), 7.88 (d, J=2.7 Hz, 1H),7.84 (dd, J=4.5, 2.4 Hz, 1H), 7.59-7.50 (m, 2H), 7.41-7.37 (m, 3H), 6.59(d, J=8.7, 1H), 6.22 (s, 1H), 5.30 (d, J=14.4 Hz, 1H), 4.67 (dd, J=14.4,3.0 Hz, 1H), 4.58 (dd, J=10.2, 3.3 Hz, 1H) 4.30 (dd, J=10.2, 6.6 Hz,1H), 3.75 (t, J=6.3 Hz, 2H), 2.70 (t, J=6.3 Hz, 2H).

Example 64 Isomer A:(R)-2-(4-(4-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)picolinoyl)piperazin-1-yl)pyrimidine-5-carbonitrileand Example 64 Isomer B:(S)-2-(4-(4-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)picolinoyl)piperazin-1-yl)pyrimidine-5-carbonitrile

Step 1: Synthesis of methyl4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-2-carboxylate

Under nitrogen, a solution of5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(500 mg, 1.13 mmol, 1.00 equiv), [Pd(allyl)Cl]₂ (42 mg, 0.10 equiv),Rockphos (53 mg, 0.10 equiv), Cs₂CO₃ (1.1 g, 3.38 mmol, 3.00 equiv) andmethyl 4-bromopyridine-2-carboxylate (488 mg, 2.26 mmol, 2.00 equiv) intoluene (40 mL) was stirred for 12 h at 80° C. The resulting solutionwas concentrated under vacuum and the residue was applied onto a silicagel column eluting with EtOAc/petroleum ether (3:1) to afford 233 mg(36%) of the title compound as a solid. LCMS (ESI, m/z): 577.20 [M+H]⁺.

Step 2: Synthesis of4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-2-carboxylicAcid

A solution of methyl 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-2-carboxylate(233 mg, 0.40 mmol, 1.00 equiv) and LiOH (48 mg, 2.00 mmol, 5.00 equiv)in water (0.5 mL) and methanol (1.5 mL) was stirred for 1 h at roomtemperature. The pH value of the solution was adjusted to 2 withhydrogen chloride (12 M) and the solids were collected by filtration toafford 271 mg (crude) of the title compound as a brown solid. LCMS (ESI,m/z): 563.19[M+H]⁺.

Step 3: Synthesis of4-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-2-carboxylicAcid Hydrochloride

A solution of4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-2-carboxylicacid (271 mg, 0.48 mmol, 1.00 equiv) in hydrogen chloride/dioxane (5 mL,4M) was stirred for 1 h at room temperature, and the resulting mixturewas concentrated under vacuum to afford 198 mg of the title compound asa solid. LCMS (ESI, m/z): 433.10[M+H]⁺.

Step 4: Synthesis of(R)-2-(4-(4-((2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)picolinoyl)piperazin-1-yl)pyrimidine-5-carbonitrileand(S)-2-(4-(4-((2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)picolinoyl)piperazin-1-yl)pyrimidine-5-carbonitrile

A solution of4-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-2-carboxylicacid hydrochloride (198 mg, 0.46 mmol, 1.00 equiv), HATU (174.116 mg,0.46 mmol, 1.00 equiv), DIPEA (177.653 mg, 1.37 mmol, 3.00 equiv) andInt-A1 (104.05 mg, 0.55 mmol, 1.20 equiv) in DMF (2 mL) was stirred for1 h at room temperature. The resulting solution was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN, and the residue wasfurther purified by Prep-HPLC and Chiral-Prep-HPLC (CHIRALPAK IG-3,0.46*10 cm; 3 um, MtBE (0.1% DEA):EtOH=70:30, 1.0 mL/min) yielding thetitle compounds. The absolute stereochemistry was assigned based on aprotein X-ray crystal structure obtained of Example 18 Isomer B whichconfirmed (S)-absolute stereochemistry and was observed to be the morepotent enantiomer.

Example 64 Isomer A

12.8 mg, 34.0%, LCMS (ESI, m/z): 604.45 [M+H]⁺, ¹HNMR (Methanol-d₄, 300MHz) δ 8.48 (s, 2H), 2.28-8.21 (m, 2H), 7.39-7.30 (m, 1H), 7.28-7.19 (m,3H), 6.99 (d, J=2.4 Hz, 1H), 6.90-6.86 (b, 1H), 6.08 (s, 1H), 2.18-5.13(m, 2H), 5.56-4.41 (m, 2H), 4.30-4.21 (m, 1H), 3.95-6.34 (m, 6H),3.41-3.31 (m, 2H), tR=3.145 min.

Example 64 Isomer B

14.5 mg, 38%, LCMS (ESI, m/z): 604.45 [M+H]⁺, tR=3.844 min

Example 65:2-[4-[(5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridin-3-yl)carbonyl]piperazin-1-yl]pyrimidine-5-carbonitrile

Step 1: Synthesis of methyl5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridine-3-carboxylate

Under nitrogen, a solution of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1.97 g, 5.01 mmol, 1.00 equiv), Cs₂CO₃ (3.25 g, 9.97 mmol, 2.00 equiv),[Pd(ally)Cl]₂ (183 mg, 0.10 equiv), RockPhos (704 mg, 0.30 equiv) andmethyl 5-bromopyridine-3-carboxylate (2.16 g, 10.00 mmol, 2.00 equiv) intoluene (40 mL) was stirred for 24 h at 80° C. The solids were filteredout, the resulting solution was concentrated under vacuum, and theresidue was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN to afford 1.28 g (48%) of the title compound as light yellowoil. LCMS (ESI, m/z): 529.20 [M+H]⁺.

Step 2: Synthesis of methyl5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridine-3-carboxylate

A solution of methyl5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridine-3-carboxylate(1.28 g, 2.42 mmol, 1.00 equiv) in hydrogen chloride/dioxane (40 mL, 4M) was stirred for 5 h at room temperature, and the resulting solutionwas concentrated under vacuum to afford 1 g of the title compound ascrude yellow oil. LCMS (ESI, m/z): 399.12 [M+H]⁺.

Step 3: Synthesis of5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridine-3-carboxylicacid

A solution of methyl5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridine-3-carboxylate(1 g, 2.26 mmol, 1.00 equiv, 90%) and LiOH (480 mg, 20.04 mmol, 8.00equiv) in methanol (30 mL) and water (3 mL) was stirred for 2 h at 25°C. The pH value of the solution was adjusted to 4 with hydrogen chloride(2 M). The resulting solution was concentrated under vacuum and theresidue was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN to afford 600 mg (69%) of the title compound as a gray solid.LCMS (ESI, m/z): 384.10 [M+H]⁺.

Step 4: Synthesis of2-[4-[(5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridin-3-yl)carbonyl]piperazin-1-yl]pyrimidine-5-carbonitrile

A solution of5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridine-3-carboxylicacid (100 mg, 0.26 mmol, 1.00 equiv), HATU (99 mg, 0.26 mmol, 1.00equiv), DIPEA (101 mg, 0.78 mmol, 3.00 equiv) and Int-A1 (49.2 mg, 0.26mmol, 1.00 equiv) in DMF (3 mL) was stirred for 1 h at room temperature.The residue was dissolved in 10 mL of H₂O, extracted with 3×20 mL ofEtOAc, and the organic layers were combined and washed with 20 mL ofbrine, dried over anhydrous sodium sulfate, and concentrated undervacuum. The residue was purified by purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN. After concentration, the residuewas further purified by Prep-HPLC yielding the title compound (25.7 mg18%) as a white solid. LCMS (ESI, m/z): 556.05 [M+H]⁺, ¹HNMR (DMSO-d₆,400 MHz,) δ 12.44 (s, 1H), 8.80 (s, 2H), 8.28 (d, J=2.8 Hz, 1H), 8.24(d, J=1.6 Hz, 1H), 8.13 (s, 1H), 7.42 (t, J=2.4 Hz, 1H), 4.82 (br, 1H),4.23-4.14 (m, 2H), 3.95-3.80 (m, 4H), 3.78-3.61 (m, 3H), 3.54-3.39 (m,2H), 3.30-3.24 (m, 1H), 2.25-2.19 (m, 1H), 1.99-1.90 (m, 1H), 1.89-1.69(m, 2H).

Example 66:6-[4-[(4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrimidin-2-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of methyl4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrimidine-2-carboxylate

A solution of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(786 mg, 2.00 mmol, 1.00 equiv), methyl 4-bromopyrimidine-2-carboxylate(561 mg, 2.59 mmol, 1.30 equiv), and potassium carbonate (1.1 g, 7.96mmol, 4.00 equiv) in DMF (10 mL) was stirred for 16 h at 80° C. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford 600 mg (57%) of thetitle compound as a solid. LCMS (ESI, m/z): 530.21 [M+H]⁺.

Step 2: Synthesis of4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrimidine-2-carboxylicAcid

A solution of methyl4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrimidine-2-carboxylate(529 mg, 1.00 mmol, 1.00 equiv), LiOH (96 mg, 4.01 mmol, 4.00 equiv),water (5 mL) in methanol (10 mL) was stirred for 2 h at roomtemperature. The pH value of the solution was adjusted to 6 withhydrogen chloride. The solvent was concentrated under vacuum and theresidue was applied onto a silica gel column eluting with ethylDCM/methanol (5:1) to afford 300 mg (58%) of the title compound as asolid. LCMS (ESI, m/z): 516.19 [M+H]⁺.

Step 3: Synthesis of6-[4-[(4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrimidin-2-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrimidine-2-carboxylicacid (260 mg, 0.50 mmol, 1.00 equiv), Int-A4 (95 mg, 0.50 mmol, 1.00equiv), EDC.HCl (288 mg, 3.00 equiv), 4-dimethylaminopyridine (244 mg,2.00 mmol, 4.00 equiv) in DMF (3 mL) was stirred for 2 h at 60° C. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford 100 mg (29%) of thetitle compound as a white solid. LCMS (ESI, m/z): 686.29 [M+H]+.

Step 4: Synthesis of6-[4-[(4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrimidin-2-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-[(4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrimidin-2-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile(100 mg, 0.15 mmol, 1.00 equiv) in hydrogen chloride/dioxane (15 mL) wasstirred for 2 h at room temperature. After concentration, the residuewas purified by C18 reverse phase chromatography eluting with H₂O/CH₃CNyielding the title compound (14.2 mg, 18%) as a white solid. LCMS (ESI,m/z): 556.25 [M+H]+, ¹HNMR (CD3OD-d4, 300 MHz) δ 8.57 (d, J=5.9 Hz, 1H),8.42 (d, J=2.3 Hz, 1H), 8.31 (s, 1H), 7.77 (dd, J=9.1, 2.4 Hz, 1H), 6.92((d, J=7.5 Hz, 1H), 6.89 (d, J=15.8 Hz, 1H), 4.76 (d, J=6.5 Hz, 1H),4.70-4.52 (m, 2H), 3.95-3.72 (m, 7H), 3.54-3.32 (m, 3H), 2.39-2.27 (m,1H), 2.07-1.93 (m, 2H), 1.92-1.77 (m, 1H).

Example 67:6-[4-[(2-fluoro-5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of methyl2-fluoro-5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate

A solution of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(500 mg, 1.27 mmol, 1.00 equiv), [Pd(allyl)Cl]₂ (443 mg, 1.21 mmol, 1.50equiv), Rockphos (60 mg, 0.13 mmol, 0.10 equiv), Cs₂CO₃ (830 mg, 2.55mmol, 2.00 equiv), methyl 5-bromo-2-fluorobenzoate (443 mg, 1.90 mmol,1.50 equiv) in toluene (14 mL) was stirred for 2 h at 80° C. in an oilbath under an atmosphere of nitrogen. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (3:7) to afford 400 mg (58%)of the title compound as a yellow solid. LCMS (ESI, m/z): 546.20 [M+H]⁺

Step 2: Synthesis of methyl2-fluoro-5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate

A solution of methyl2-fluoro-5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate(400 mg, 0.73 mmol, 1.00 equiv) in hydrogen chloride/dioxane (20 mL) wasstirred for 14 h at room temperature. The resulting solution wasconcentrated under vacuum to afford 320 mg crude of the title compoundas yellow crude oil. LCMS (ESI, m/z): 416.12 [M+H]⁺.

Step 3: Synthesis of2-fluoro-5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicAcid

A solution of methyl2-fluoro-5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate(320 mg, 0.77 mmol, 1.00 equiv), LiOH.H₂O (162 mg, 3.86 mmol, 5.00equiv) in methanol (20 mL) and water (5 mL) was stirred for 2 h at roomtemperature. The resulting mixture was concentrated under vacuum. The pHvalue of the solution was adjusted to 6 with hydrogen chloride (2 M).The solids were collected by filtration and dried in an oven underreduced pressure. This resulted in 240 mg (78%) of the title compound asa yellow solid. LCMS (ESI, m/z): 402.10 [M+H]⁺.

Step 4: Synthesis of6-[4-[(2-fluoro-5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of2-fluoro-5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicacid (240 mg, 0.60 mmol, 1.00 equiv), Int-A4 (161 mg, 0.86 mmol, 1.20equiv), DIPEA (232 mg, 1.80 mmol, 3.00 equiv), HATU (250 mg, 0.66 mmol,1.10 equiv) in DMF (4 mL) was stirred for 2 h at room temperature. Thecrude product was purified by C18 reverse phase column eluting withwater ACN/water. The residue was further purified by Prep-HPLC yieldingthe title compound (64.2 mg, 19%) as a white solid. LCMS (ESI, m/z):572.20 [M+H]⁺¹, ¹H NMR (Methanol-d₄, 300 MHz) δ: 8.42 (dd, J=2.4, 0.7Hz, 1H), 8.20 (s, 1H), 7.76 (dd, J=9.1, 2.4 Hz, 1H), 7.13 (t, J=9.0 Hz,1H), 7.01 (dt, J=9.1, 3.8 Hz, 1H), 6.95-6.84 (m, 2H), 4.19 (dd, J=10.2,3.7 Hz, 1H), 4.02 (dd, J=10.2, 6.8 Hz, 1H), 3.91-3.90-3.85 (m, 4H),3.76-3.69 (m, 3H), 3.50-3.35 (m, 3H), 2.39-2.29 (m, 1H), 2.10-2.00 (m,1H), 1.97-1.75 (m, 1H), 1.90-1.70 (m, 2H).

Example 68:6-[4-[(2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrimidin-4-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of methyl2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrimidine-4-carboxylate

A solution of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(500 mg, 1.27 mmol, 1.00 equiv), (Pd(allyl)C)₂ (47 mg, 0.10 equiv),Rockphos (60 mg, 0.10 equiv), Cs₂CO₃ (829 mg, 2.54 mmol, 2.00 equiv),methyl 2-chloropyrimidine-4-carboxylate (547 mg, 3.17 mmol, 2.50 equiv)in toluene (10 mL) under nitrogen atmosphere was stirred overnight at85° C. The solvent was concentrated under vacuum and the residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(3/7) to afford 425 mg (63%) of the title compound as a yellow solid.LCMS (ESI, m/z): 530.20 [M+H]⁺.

Step 2: Synthesis of methyl2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrimidine-4-carboxylate

A solution of methyl2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrimidine-4-carboxylate(425 mg, 0.80 mmol, 1.00 equiv) in dioxane/HCl (20 mL, 4 M) was stirredfor overnight at 25° C. The solvent was concentrated under vacuum toafford 290 mg (91%) of the title compound as yellow oil. LCMS (ESI,m/z): 400.12 [M+H]⁺

Step 3: Synthesis of2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrimidine-4-carboxylicAcid

A solution of methyl2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrimidine-4-carboxylate(360 mg, 0.90 mmol, 1.00 equiv), LiOH.H₂O (285 mg, 6.79 mmol, 10.00equiv) in MeOH (10 mL) and water (2 mL) was stirred for 2 h at 25° C.The resulting solution was concentrated under vacuum. The residue wasdiluted with 3 mL of water, and the pH value of the solution wasadjusted to 3 with hydrogen chloride (2M). The residue was purified byC18 reverse phase chromatography eluting with H₂O/CH₃CN to afford 70 mg(20%) of the title compound as a off-white solid. LCMS (ESI, m/z):386.10 [M+H]⁺.

Step 4: Synthesis of6-[4-[(2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrimidin-4-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrimidine-4-carboxylicacid (60 mg, 0.16 mmol, 1.00 equiv), HOBt (45 mg, 0.33 mmol, 1.50equiv), EDCI (32 mg, 0.17 mmol, 1.50 equiv), DIPEA (60 mg, 0.46 mmol,3.00 equiv), Int-A4 (70 mg, 0.37 mmol, 2.00 equiv) in DMF (3 mL) wasstirred for overnight at 25° C. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN. Theresidue was further purified by Prep-HPLC yielding the title compound(16.5 mg, 19%) as a white solid. LCMS (ESI, m/z): 556.20 [M+H]⁺, ¹H NMR(DMSO-d₆, 300 MHz) δ: 12.43 (s, 1H), 8.71 (d, J=4.9 Hz, 1H), 8.50 (d,J=2.2 Hz, 1H), 8.17 (s, 1H), 7.89 (dd, J=9.1, 2.3 Hz, 1H), 7.28 (d,J=4.9 Hz, 1H), 6.92 (d, J=9.3 Hz, 1H), 4.74 (s, 1H), 4.62-4.49 (m, 1H),4.45-4.33 (m, 1H), 3.88-3.57 (m, 7H), 3.47-3.39 (m, 2H), 3.27-3.18 (m,1H), 2.26-2.11 (m, 1H), 1.98-1.88 (m, 2H), 1.75-1.63 (m, 1H).

Example 69:6-[4-[(2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridin-4-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of methyl2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridine-4-carboxylate

A solution of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(400 mg, 1.02 mmol, 1.00 equiv), methyl 2-bromopyridine-4-carboxylate(328 mg, 1.52 mmol, 1.50 equiv), Pd[(allyl)Cl]₂ (37.3 mg, 0.10 mmol,0.10 equiv), Rockphos (95.5 mg, 0.20 equiv) and Cs₂CO₃ (664 mg, 2.04mmol, 2.00 equiv) in toluene (15 mL) was stirred for 15 h at 80° C. inan oil bath. The solid was filtered out and the resulting solution wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with eluting EtOAc/petroleum ether (31/69) to afford 237 mg (44%)of the title compound as a solid. LCMS (ESI, m/z): 529.20 [M+H]⁺.

Step 2: Synthesis of methyl2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridine-4-carboxylateHydrochloride

A solution of methyl2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridine-4-carboxylate(237 mg, 0.45 mmol, 1.00 equiv) in hydrogen chloride/dioxane (10 mL, 4M)was stirred for 2 h at room temperature, and the resulting solution wasconcentrated under vacuum to afford 195 mg of the title compound as acrude yellow solid. LCMS (ESI, m/z): 399.12 [M+H]⁺.

Step 3: Synthesis of2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridine-4-carboxylicAcid

A solution of methyl2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridine-4-carboxylate(175 mg, 0.44 mmol, 1.00 equiv) and LiOH (42.2 mg, 1.76 mmol, 4.00equiv) in water (2.5 mL) and THF (10 mL) was stirred for 2 h at roomtemperature. The resulting solution was concentrated under vacuum, andthe residue was diluted with 10 mL of H₂O, and the pH value of thesolution was adjusted to 4 with hydrogen chloride (36%). The solids werecollected by filtration to afford 138 mg (82%) of the title compound asa yellow solid. LCMS (ESI, m/z): 385.10[M+H]⁺.

Step 4: Synthesis of6-[4-[(2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridin-4-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridine-4-carboxylicacid (118 mg, 0.31 mmol, 1.00 equiv), HATU (116.7 mg, 0.31 mmol, 1.00equiv), DIPEA (118.9 mg, 0.92 mmol, 3.00 equiv) and Int-A4 (58 mg, 0.31mmol, 1.00 equiv) in DMF (4 mL) was stirred for 40 min at roomtemperature. The resulting solution was dissolved in 20 mL of H₂O andextracted with 3×20 mL of EtOAc. The organic layers were combined anddried over anhydrous sodium sulfate and then concentrated under vacuum,and the residue was purified by Prep-HPLC yielding the title compound(18.0 mg, 11%) as a white solid. LCMS (ESI, m/z): 555.20 [M+H]+, 1H NMR(DMSO-d₆, 400 MHz,) δ 12.44 (s, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.20-8.16(m, 2H), 7.92 (dd, J=9.2, 2.4 Hz, 1H), 7.02 (dd, J=5.2, 1.2 Hz, 1H),6.96 (d, J=8.8 Hz, 1H), 6.74 (s, 1H), 4.79-4.73 (m, 1H), 4.51-4.47 (m,1H), 4.41-4.36 (m, 1H), 3.80-3.57 (m, 7H), 3.33-3.21 (m, 3H), 2.21-2.19(m, 1H), 1.97-1.69 (m, 3H).

Example 70:6-[4-[(3-[[(2S,4S)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of [(2S,4S)-4-methylpyrrolidin-2-yl]methanolHydrochloride

A solution of tert-butyl(2S,4S)-2-(hydroxymethyl)-4-methylpyrrolidine-1-carboxylate (1 g, 4.64mmol, 1.00 equiv) in dioxane/HCl (8 mL) was stirred for 2 h at 25° C.The resulting mixture was concentrated under vacuum to afford 520 mg(crude) of the title compound as crude colorless oil. LCMS (ESI, m/z):116.10 [M−Cl]⁺.

Step 2: Synthesis of5-[(2S,4S)-2-(hydroxymethyl)-4-methylpyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of Int-A6 (1 g, 3.04 mmol, 1.00 equiv),[(2S,4S)-4-methylpyrrolidin-2-yl]methanol hydrochloride (520 mg, 3.43mmol, 1.00 equiv) in ethanol (10 mL) and TEA (5 mL) was stirred for 60min at 60° C. After concentration, the residue was applied onto a silicagel column eluting with EtOAc/petroleum ether (1/2) to afford 900 mg(73%) of the title compound as a white solid. LCMS (ESI, m/z): 408.19[M+H]⁺.

Step 3: Synthesis of methyl3-[[(2S,4S)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate

Under nitrogen, a solution of5-[(2S,4S)-2-(hydroxymethyl)-4-methylpyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(900 mg, 2.21 mmol, 1.00 equiv), methyl 3-bromobenzoate (946 mg, 4.40mmol, 2.00 equiv), Pd(dba)CHCl₃ (228 mg, 0.10 equiv), Rockphos (104 mg,0.10 equiv), Cs₂CO₃ (2.16 g, 6.63 mmol, 3.00 equiv) in toluene (50 mL)was stirred overnight at 80° C. After concentration, the residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(2/3) to afford 700 mg (59%) of the title compound as yellow oil. LCMS(ESI, m/z): 542.22 [M+H]⁺.

Step 4: Synthesis of methyl3-[[(2S,4S)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate

A solution of methyl3-[[(2S,4S)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate(700 mg, 1.29 mmol, 1.00 equiv) in dioxane/HCl (10 mL) was stirred for 6h at 25° C. After concentration, the residue was purified by C18 reversephase chromatography eluting with H₂O/CH₃CN (1/1) to afford 300 mg (56%)of the title compound as a yellow solid. LCMS (ESI, m/z): 412.14 [M+H]⁺.

Step 5: Synthesis of3-[[(2S,4S)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicAcid

A solution of methyl3-[[(2S,4S)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate(300 mg, 0.73 mmol, 1.00 equiv), LiOH (96 mg, 4.01 mmol, 5.00 equiv) inTHF (10 mL) and water (2 mL) was stirred overnight at 25° C. The pHvalue was adjusted to 3 with hydrogen chloride (1 M). The resultingsolution was extracted with 2×50 mL of DCM and the organic layers werecombined and concentrated under vacuum to afford 100 mg (35%) of thetitle compound as a yellow solid. LCMS (ESI, m/z): 398.12 [M+H]⁺.

Step 6: Synthesis of6-[4-[(3-[[(2S,4S)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-[[(2S,4S)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicacid (100 mg, 0.25 mmol, 1.00 equiv), HATU (96 mg, 0.25 mmol, 1.00equiv), DIPEA (65 mg, 0.50 mmol, 2.00 equiv), Int-A4 (47 mg, 0.25 mmol,1.00 equiv) in DMF (2 mL) was stirred overnight at 25° C. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN yielding the title compound (56.1mg 39%) as a white solid. LCMS (ESI, m/z): 568.22 [M+H]⁺, ¹H NMR(Methanol-d₄, 400 MHz) δ: 8.42 (dd, J=2.3, 0.8 Hz, 1H), 8.21 (s, 1H),7.77-7.74 (dd, J=9.1, 2.4 Hz, 1H), 7.40-7.36 (t, J=7.9 Hz, 1H),7.04-7.00 (m, 2H), 6.94-6.87 (m, 2H), 4.24-4.21 (dd, J=10.3, 3.5 Hz,1H), 4.07-4.03 (dd, J=10.3, 6.8 Hz, 1H), 3.83 (dr, 4H), 3.77-3.35 (m,2H), 3.41-3.35 (m, 2H), 2.43-2.40 (m, 3H), 2.21-2.19 (m, 1H), 1.55-1.47(m, 1H), 1.14-1.22 (d, J=6.3 Hz, 3H).

Example 71:6-(4-[[3-([4-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]morpholin-3-yl]methoxy)phenyl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1: Synthesis of5-[3-(hydroxymethyl)morpholin-4-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1000 mg, 3.04 mmol, 1 equiv), piperidin-2-ylmethanol hydrochloride(922.4 mg, 6.08 mmol, 2 equiv), TEA (923.3 mg, 9.12 mmol, 3 equiv) inEtOH (10 mL) was stirred for 4 h at 60° C. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (80/20) to afford 442 mg(35.49%) of the title compound as a yellow solid. LCMS (ESI, m/z):410.16 [M+H]⁺.

Step 2: Synthesis of methyl3-([4-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]morpholin-3-yl]methoxy)benzoate

A solution of5-[3-(hydroxymethyl)morpholin-4-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(420 mg, 1.03 mmol, 1 equiv), [Pd(allyl)Cl]₂ (37 mg, 0.10 mmol, 0.099equiv), Rockphos (48.1 mg, 0.10 mmol, 0.1 equiv), Cs₂CO₃ (668.4 mg, 2.05mmol, 2 equiv), methyl 3-bromobenzoate (286.7 mg, 1.33 mmol, 1.3 equiv)in toluene (5 mL) under an inert atmosphere of nitrogen was stirred for6 h at 80° C. After concentration, the residue was applied onto a silicagel column eluting with EtOAc/petroleum ether (43/57) to afford 427 mg(76.58%) of the title compound as red oil. LCMS (ESI, m/z): 544.20[M+H]⁺.

Step 3: Synthesis of methyl3-([4-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]morpholin-3-yl]methoxy)benzoateHydrochloride

A solution of methyl3-([4-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]morpholin-3-yl]methoxy)benzoate(427 mg) in HCl/dioxane (5 mL) was stirred for 24 h at room temperature.The resulting mixture was concentrated under vacuum. This resulted in353 mg of the title compound as yellow oil. LCMS (ESI, m/z): 414.12[M+H]⁺.

Step 4: Synthesis of3-([4-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]morpholin-3-yl]methoxy)benzoicAcid

A solution of methyl3-([4-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]morpholin-3-yl]methoxy)benzoate(353 mg, 0.85 mmol, 1 equiv), LiOH.H₂O (165.0 mg, 3.93 mmol, 4.604equiv) in MeOH (4 mL) and H₂O (1 mL) was stirred for 5 h at roomtemperature. The resulting solution was diluted with 5 mL of H₂O, andthe pH value of the solution was adjusted to 6 with HCl (40%). Thesolids were collected by filtration. This resulted in 254 mg (74.48%) ofthe title compound as a white solid. LCMS (ESI, m/z): 400.10 [M+H]⁺.

Step 5: Synthesis of6-(4-[[3-([4-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]morpholin-3-yl]methoxy)phenyl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of3-([4-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]morpholin-3-yl]methoxy)benzoicacid (244 mg, 0.61 mmol, 1 equiv), DIPEA (236.9 mg, 1.83 mmol, 3 equiv),HATU (255.6 mg, 0.67 mmol, 1.1 equiv), Int-A4 (151.0 mg, 0.67 mmol, 1.1equiv) in DMF (5 mL) was stirred for 5 h at room temperature. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN. The residue was further purifiedby Prep-HPLC yielding the title compound (137.2 mg, 39.42%) as a whitesolid. LCMS (ESI, m/z): 570.20 [M+H]+, ¹H NMR (300 MHz, DMSO-d6) δ:12.72 (s, 1H), 8.53 (d, J=2.3 Hz, 1H), 8.01 (s, 1H), 7.91 (dd, J=9.1,2.4 Hz, 1H), 7.34 (t, J=7.8 Hz, 1H), 7.04-6.91 (m, 2H), 6.86 (d, J=9.6Hz, 2H), 4.44-4.33 (t, J=9.9 Hz, 2H), 4.11 (s, 1H), 3.93 (t, J=13.4 Hz,2H), 3.69 (d, J=11.2 Hz, 7H), 3.55 (d, J=11.2 Hz, 4H), 3.19 (d, J=12.4Hz, 1H).

Example 72 Isomer A:6-[4-[(6-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]pyrazin-2-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrileand Example 72 Isomer B:6-[4-[(6-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]pyrazin-2-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of methyl6-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrazine-2-carboxylate

A solution of5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(500 mg, 1.13 mmol, 1.00 equiv), [Pd(ally)Cl]₂ (42 mg, 0.11 mmol, 0.10equiv), Rockphos (53 mg, 0.11 mmol, 0.10 equiv), methyl6-bromopyrazine-2-carboxylate (490 mg, 2.26 mmol, 2.00 equiv), Cs₂CO₃(740 mg, 2.27 mmol, 2.00 equiv) in toluene (7 mL) was stirred for 5 hunder an atmosphere of nitrogen at 80° C. The reaction mixture wasconcentrated under vacuum and the residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (4/6) to afford 555 mg (85%)of the title compound as a yellow solid. LCMS (ESI, m/z): 578.20 [M+H]⁺.

Step 2: Synthesis of6-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrazine-2-carboxylicAcid

A solution of6-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrazine-2-carboxylate(555 mg, 0.96 mmol, 1.00 equiv), LiOH hydrate (202 mg, 4.81 mmol, 5.00equiv) in THF (15 mL) and water (3 mL) was stirred for 2 h at roomtemperature. The resulting mixture was concentrated under vacuum. The pHvalue of the solution was adjusted to 6 with hydrochloric acid (1 M).The solids were collected by filtration to afford 468 mg (86%) of thetitle compound as an off-white solid. LCMS (ESI, m/z): 564.18 [M+H]⁺.

Step 3: Synthesis of6-(4-[[6-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrazin-2-yl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrazine-2-carboxylicacid (220 mg, 0.39 mmol, 1.00 equiv), Int-A4 (88 mg, 0.39 mmol, 1.00equiv), DIPEA (151 mg, 1.17 mmol, 3.00 equiv), HATU (223 mg, 0.59 mmol,1.50 equiv) in DMF (3 mL) was stirred for 1.5 h at room temperature. Theresulting solution was purified by C18 reverse phase chromatographyeluting with H₂O/CH₃CN to afford 133 mg (46%) of the title compound as awhite solid. LCMS (ESI, m/z): 734.28 [M+H]⁺

Step 4: Synthesis of6-[4-[(6-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]pyrazin-2-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(6-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]pyrazin-2-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of 6-(4-[[6-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrazin-2-yl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrilein hydrogen chloride/dioxane (7 mL) was stirred for 4 h at roomtemperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN. The residue wasfurther purified by Prep-HPLC and Chiral-Prep-HPLC (CHIRALPAK IC-3,0.46*5 cm; 3 um, (Hex:DCM=1:1) (0.1% DEA):(MeOH:EtOH=1:1)=30:70, 1.0mL/min) yielding the title compounds as white solids. The absolutestereochemistry was assigned based on a protein X-ray crystal structureobtained of Example 18 Isomer B which confirmed (S)-absolutestereochemistry and was observed to be the more potent enantiomer.

Example 72 Isomer A

12 mg, 34%, LCMS (ESI, m/z): 604.55 [M+H]⁺, ¹H NMR (400 MHz,Methanol-d4) δ: 8.48-8.38 (m, 3H), 8.27 (s, 1H), 7.79 (dd, J=9.1, 2.4Hz, 1H), 7.50 (d, J=6.2 Hz, 1H), 7.44-7.34 (m, 3H), 6.89 (dd, J=9.1, 0.8Hz, 1H), 6.14 (s, 1H), 5.23 (d, J=14.7 Hz, 1H), 4.99 (dd, J=11.6, 4.6Hz, 1H), 4.75-4.61 (m, 2H), 3.89 (m, 4H), 3.76 (d, J=5.8 Hz, 2H), 3.69(d, J=5.3 Hz, 2H). tR=3.172 min.

Example 72 Isomer B

11.5 mg, 33%, LCMS (ESI, m/z): 604.55 [M+H]⁺, tR=4.791 min.

Example 73:6-[4-[(4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridin-2-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of methyl4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridine-2-carboxylate

A solution of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(360 mg, 0.91 mmol, 1.00 equiv), [Pd(allyl)Cl]₂ (35.519 mg, 0.10 equiv),Rockphos (42.94164 mg, 0.09 mmol, 0.10 equiv), methyl4-bromopyridine-2-carboxylate (393.649 mg, 1.82 mmol, 2.00 equiv) andCs₂CO₃ (895.45 mg, 3.00 equiv) in toluene (15 mL) was stirred for 5 h at80° C. under an atmosphere of nitrogen. The resulting solution wasconcentrated under vacuum and the residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (1:3) to afford 210 mg (43%)of the title compound as a yellow oil. LCMS (ESI, m/z): 529.20[M+H]⁺.

Step 2: Synthesis of4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridine-2-carboxylicacid

A solution of methyl4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridine-2-carboxylate(189 mg, 0.36 mmol, 1.00 equiv) and LiOH (25.7726 mg, 1.08 mmol, 3.00equiv) in water (4 mL) and THF (16 mL) was stirred for 2 h at roomtemperature. The pH value of the solution was adjusted to 2 withhydrogen chloride (12 M) and the solids were collected by filtration toafford 160 mg (87%) of the title compound as a solid. LCMS (ESI, m/z):515.19[M+H]⁺.

Step 3: Synthesis of4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridine-2-carboxylicAcid

A solution of4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridine-2-carboxylicacid (160 mg, 0.31 mmol, 1.00 equiv) in hydrogen chloride/dioxane (5 mL,4 M) was stirred for 3 h at room temperature, and the resulting solutionwas concentrated under vacuum to afford 85 mg (71%) of the titlecompound as a solid. LCMS (ESI, m/z): 385.10[M+H]⁺.

Step 4: Synthesis of6-[4-[(4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridin-2-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridine-2-carboxylicacid (15 mg, 0.04 mmol, 1.00 equiv), HATU (14.82 mg, 1.00 equiv), DIPEA(15.12108 mg, 3.00 equiv) and Int-A4 (8.8125 mg, 0.05 mmol, 1.20 equiv)in DMF (2 mL) was stirred for 2 h at room temperature. The resultingsolution was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN. After concentrating the residue was further purified byPrep-HPLC yielding the title compound (12 mg, 3.0%) as a white solid.LCMS (ESI, m/z): 555.10 [M+H]⁺. ¹HNMR (Methanol-d₄, 400 MHz) δ 8.44 (dd,J=8.8, 3.2 Hz, 2H), 8.22 (s, 1H), 7.79 (dd, J=9.2, 2.4 Hz, 1H), 7.156(s, 1H), 7.07 (dd, J=5.6, 2.4 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 4.95-4.91(m, 1H), 4.37 (dd, J=10.4, 3.6 Hz, 1H), 4.24 (dd, J=10.4, 6.4 Hz, 1H),3.92-3.84 (m, 4H), 3.76-3.74 (m, 3H), 3.55 (t, J=5.2 Hz, 2H), 3.47-3.38(m, 1H), 2.39 (m, 1H), 2.08 (t, J=5.6 Hz, 1H), 1.99-1.78 (m, 2H).

Example 74:6-[4-[(6-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrazin-2-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of6-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrazine-2-carboxylate

A solution of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(700 mg, 1.78 mmol, 1 equiv), K₂CO₃ (740 mg, 5.35 mmol, 3.010 equiv),methyl 6-bromopyrazine-2-carboxylate (464 mg, 2.14 mmol, 1.202 equiv) inDMF (15 mL) was stirred for 12 h at 90° C. The reaction was quenched bythe addition of 5 mL of water. The resulting solution was extracted with3×20 ml of EtOAc and the organic layers were combined and concentratedunder vacuum. The residue was applied onto a silica gel column elutingwith EtOAc/petroleum ether (25/75) to afford 500 mg (53.07%) of thetitle compound as yellow oil. LCMS (ESI, m/z): 530.20 [M+H]⁺.

Step 2: Synthesis of6-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrazine-2-carboxylicAcid

A solution of methyl6-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrazine-2-carboxylate(500 mg, 0.94 mmol, 1 equiv), LiOH.H₂O (198 mg, 4.72 mmol, 4.998 equiv)in MeOH (20 mL) was stirred for 2 h at room temperature. The resultingsolution was extracted with 2×15 ml of EtOAc. The pH value of thesolution was adjusted to 5 with HCl (35%). The resulting solution wasextracted with 3×30 mL of DCM and the organic layers combined and driedover anhydrous sodium sulfate. The organic layers was concentrated undervacuum to afford 400 mg (crude) of the title compound as yellow oil.LCMS (ESI, m/z): 516.18 [M+H]⁺.

Step 3: Synthesis of6-[4-[(6-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrazin-2-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrazine-2-carboxylicacid (270 mg, 0.52 mmol, 1 equiv), Int-A4 (118.7 mg, 0.63 mmol, 1.204equiv), DIPEA (202 mg, 1.56 mmol, 2.984 equiv), HATU (298 mg, 0.78 mmol,1.497 equiv) in DMF (2 mL) was stirred for 2 h at room temperature.After concentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford 300 mg (83.53%) of thetitle compound as yellow oil. LCMS (ESI, m/z): 686.28 [M+H]⁺.

Step 4: Synthesis of6-[4-[(6-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrazin-2-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-[(6-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrazin-2-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile(300 mg, 0.44 mmol, 1 equiv) in HCl/dioxane (10 ml) was stirred for 12 hat room temperature. After concentration, the residue was purified byC18 reverse phase chromatography eluting with H₂O/CH₃CN. Then theresidue was further purified by Prep-HPLC yielding the title compound(48.0 mg, 19.75%) as a white solid. LCMS (ESI, m/z): 556.51 [M+H]⁺,¹HNMR (DMSO-d₆, 300 MHz) δ: 12.48 (s, 1H), 8.53 (d, J=2.3 Hz, 1H), 8.45(s, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 7.92 (dd, J=9.1, 2.4 Hz, 1H), 6.94(d, J=9.1 Hz, 1H), 4.60 (dd, J=11.4, 5.0 Hz, 1H), 4.39 (dd, J=11.4, 4.2Hz, 1H), 3.88-3.79 (m, 1H), 3.87-3.81 (m, 6H), 3.41-3.30 (m, 3H), 3.24(t, J=8.7 Hz, 1H), 2.28-2.16 (m, 1H), 1.95 (m, 2H), 1.79-1.68 (m, 1H).

Example 75:6-[4-[(3-[[(2S,4R)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl(2S,4R)-2-(hydroxymethyl)-4-methylpyrrolidine-1-carboxylate

To a stirred solution of(2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid(1.8 g, 7.85 mmol, 1.00 equiv) in THF (20 mL) BH₃-THF (10 mL) was addeddropwise at 0° C. The resulting solution was stirred for 2 h at roomtemperature. The reaction was then quenched by the addition of 10 mL ofmethanol. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with EtOAc/petroleum ether(2:3). This resulted in 1.4 g (83%) of the title compound as a solid.LCMS (ESI, m/z): 216.16 [M+H]⁺.

Step 2: Synthesis of [(2S,4R)-4-methylpyrrolidin-2-yl]methanol

A solution of tert-butyl(2S,4R)-2-(hydroxymethyl)-4-methylpyrrolidine-1-carboxylate (1.4 g, 6.50mmol, 1.00 equiv) in hydrogen chloride/dioxane (10 mL) was stirred for 1h at room temperature. The resulting mixture was concentrated undervacuum. This resulted in 1 g (crude) of the title compound as oil. LCMS(ESI, m/z): 116.11 [M+H]⁺.

Step 3: Synthesis of5-[(2S,4R)-2-(hydroxymethyl)-4-methylpyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of [(2S,4R)-4-methylpyrrolidin-2-yl]methanol hydrochloride (1g, 6.59 mmol, 1.00 equiv), Int-A6 (2.1 g, 6.39 mmol, 0.97 equiv) and TEA(3 mL) in ethanol (15 mL) was stirred for 1 h at 60° C. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column with EtOAc/petroleum ether (1:1). This resulted in 1.5g (56%) of the title compound as a solid. LCMS (ESI, m/z): 408.19[M+H]⁺.

Step 4: Synthesis of methyl3-[[(2S,4R)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate

A solution of5-[(2S,4R)-2-(hydroxymethyl)-4-methylpyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethyl-silyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(850 mg, 2.09 mmol, 1.00 equiv), methyl 3-bromobenzoate (900 mg, 4.19mmol, 2.01 equiv), Pd₂(dba)₃.CHCl₃ (217 mg), Rockphos (200 mg) andCs₂CO₃ (2 g, 6.14 mmol, 2.94 equiv) in toluene (10 mL) was stirredovernight at 80° C. under an inert atmosphere of nitrogen. The resultingsolution was diluted with 200 mL of EtOAc. The resulting mixture waswashed with 50 mL of water and 50 mL of brine. The organic layer wasdried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was applied onto a silica gel column with EtOAc/petroleum ether(1:1). This resulted in 1 g (89%) of the title compound as oil. LCMS(ESI, m/z): 542.23 [M+H]⁺.

Step 5: Synthesis of3-[[(2S,4R)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicAcid

To a stirred solution of methyl3-[[(2S,4R)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethyl-silyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate(1 g, 1.85 mmol, 1.00 equiv) in THF (15 mL) and water (5 mL), LiOH (250mg, 10.44 mmol, 5.65 equiv) was added. The resulting solution wasstirred overnight at room temperature. The pH of the solution wasadjusted to 1 with hydrogen chloride (1 M). The resulting solution wasdiluted with 250 mL of EtOAc. The resulting mixture was washed with 50mL of brine. The organic layer was dried over anhydrous sodium sulfateand concentrated under vacuum. This resulted in 900 mg (92%) of thetitle compound as a solid. LCMS (ESI, m/z): 528.21 [M+H]⁺.

Step 6: Synthesis of3-[[(2S,4R)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicAcid

A solution of3-[[(2S,4R)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicacid (350 mg, 0.66 mmol, 1.00 equiv) in hydrogen chloride/dioxane (10mL) was stirred for 6 h at room temperature. The resulting mixture wasconcentrated under vacuum. This resulted in 250 mg (crude) of the titlecompound as a solid. LCMS (ESI, m/z): 398.13 [M+H]⁺.

Step 7: Synthesis of6-[4-[(3-[[(2S,4R)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

To a stirred solution of3-[[(2S,4R)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoicacid (250 mg, 0.63 mmol, 1.00 equiv) in DMF (10 mL), DIPEA (0.5 mL),Int-A4 (154 mg, 0.82 mmol, 1.30 equiv) and HATU (310 mg, 0.82 mmol, 1.30equiv) were added. The resulting solution was stirred overnight at roomtemperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN. The residue wasfurther purified by Prep-HPLC yielding the title compound (48.2 mg, 13%)as a white solid. LCMS (ESI, m/z): 568.30 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 12.45 (s, 1H), 8.49 (d, J=2.2 Hz, 1H), 8.17 (s, 1H), 7.88(dd, J=9.1, 2.4 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H), 6.99-6.86 (m, 4H),4.96-4.86 (m, 1H), 4.12 (dd, J=10.2, 4.0 Hz, 1H), 3.99 (dd, J=10.3, 6.2Hz, 1H), 3.89-3.52 (m, 8H), 3.41-3.37 (m, 1H), 2.88 (d, J=10.8 Hz, 1H),2.45-2.36 (m, 1H), 1.98-1.89 (m, 1H), 1.88-1.78 (m, 1H), 0.85 (d, J=6.9Hz, 3H).

Example 76:6-[4-(2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]acetyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]acetate

To a solution of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(10 g, 25.41 mmol, 1.00 equiv) and Cs₂CO₃ (41 g, 125.84 mmol, 5.00equiv) in DMF (150 mL) was added tert-butyl 2-chloroacetate (38 g,252.32 mmol, 10.00 equiv), and the resulting solution was stirred for 20h at 60° C. The solids were filtered out, and the resulting solution wasdiluted with 200 mL of EtOAc, washed with 3×200 mL of water and 2×200 mLof sodium chloride. The organic layer was dried over anhydrous sodiumsulfate and concentrated under vacuum, and the residue was applied ontoa silica gel column eluting with EtOAc/petroleum ether (18:82) to afford4.5 g (35%) of the title compound as brown oil. LCMS (ESI, m/z):508.24[M+H]⁺.

Step 2: Synthesis of2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]aceticAcid

A solution of tert-butyl2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]acetate(1.5 g, 2.95 mmol, 1.00 equiv) and TFA (3 mL) in DCM (15 mL) was stirredfor 2 h at room temperature. The resulting solution was concentratedunder vacuum, and the residue was further purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford 504 mg (53%) of thetitle compound as brown oil. LCMS (ESI, m/z): 322.09[M+H]⁺.

Step 4: Synthesis of6-[4-(2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]acetyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]aceticacid (115 mg, 0.36 mmol, 1.00 equiv), HATU (136 mg, 0.36 mmol, 1.00equiv), DIPEA (92 mg, 0.71 mmol, 2.00 equiv) and Int-A4 (80 mg, 0.43mmol, 1.20 equiv) in DMF (1 mL) was stirred for 2 h at room temperature.The resulting solution was purified by C18 reverse phase chromatographyeluting with H₂O/CH₃CN and Prep-HPLC yielding the title compound (11 mg,6.0%) as a white solid. LCMS (ESI, m/z): 492.15[M+H]⁺. ¹H NMR(Methanol-d₄, 300 MHz) δ 8.41 (d, J=2.4, 1H), 8.20 (s, 1H), 7.78 (dd,J=9.0, 2.4 Hz, 1H), 6.85 (d, J=9.3 Hz, 1H), 4.69 (s, 1H), 4.27 (s, 2H),3.77-3.64 (m, 8H), 3.62-3.50 (m, 3H), 3.40-3.36 (m, 1H), 2.28 (t, J=6.0Hz, 1H), 1.99 (d, J=4.8 Hz, 1H), 1.80-1.68 (m, 2H).

Example 77:6-[4-(4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of methyl(2E)-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-2-enoate

A solution of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(600 mg, 1.52 mmol, 1.00 equiv), methyl (2E)-4-bromobut-2-enoate (1.358g, 7.59 mmol, 5.00 equiv), [Pd(allyl)Cl]₂ (28 mg, 0.08 mmol, 0.05equiv), Rockphos (71 mg, 0.15 mmol, 0.10 equiv) and Cs₂CO₃ (995 mg, 3.05mmol, 2.00 equiv) in toluene (16 mL) was stirred for 12 h at 80° C. Theresulting solution was concentrated under vacuum, and the residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(2:3) to afford 400 mg (53%) of the title compound as a light yellowsolid. LCMS (ESI, m/z): 492.21 [M+H]⁺.

Step 2: Synthesis of methyl4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoate

A solution of methyl(2E)-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-2-enoate(400 mg, 0.81 mmol, 1.00 equiv) and Pd/C (40 mg, 0.10 equiv) in methanol(10 mL) was stirred for 1 h at room temperature under an atmosphere ofhydrogen. The solids were filtered out and the resulting solution wasconcentrated under vacuum to afford 380 mg (95%) of the title compoundas a light brown solid. LCMS (ESI, m/z): 494.23 [M+H]⁺.

Step 3: Synthesis of methyl(S)-4-((1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)butanoate

A solution of methyl4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoate(370 mg, 0.75 mmol, 1.00 equiv) and TFA (1 mL) in DCM (5 mL) was stirredfor 45 min at room temperature, and the resulting solution wasconcentrated under vacuum to afford 357 mg of the title compound as a acrude light brown solid. LCMS(ESI, m/z): 364.14 [M+H]⁺.

Step 4: Synthesis of(S)-4-((1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)butanoicAcid

A solution of methyl4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoate(350 mg, 0.96 mmol, 1.00 equiv) and LiOH (115.70 mg, 4.83 mmol, 5.00equiv) in water (2 mL) and THF (8 mL) was stirred for 40 min at roomtemperature, and then the resulting solution was concentrated undervacuum. The pH value of the solution was adjusted to 4 with HCl (1 M).The resulting solution was extracted with 3×10 ml of EtOAc and theorganic layer were combined and concentrated under vacuum to afford 350mg of the title compound crude as a a light brown solid. LCMS(ESI, m/z):350.13 [M+H]+.

Step 3: Synthesis of6-[4-(4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoicacid (300 mg, 0.86 mmol, 1.00 equiv), Int-A4 (177.24 mg, 0.94 mmol, 1.10equiv), HATU (325.698 mg, 0.86 mmol, 1.00 equiv) and DIPEA (332.31 mg,2.57 mmol, 3.00 equiv) in DMF (2 mL) was stirred for 4 h at 80° C. Theresulting solution was diluted with 20 ml of water, extracted with 3×20ml of EtOAc and the organic layers were combined, washed with 20 ml ofbrine and concentrated under vacuum, and the residue was purified byPrep-HPLC yielding the title compound (135 mg, 30%) as a white solid.LCMS (ESI, m/z): 520.10 [M+H]+, ¹HNMR (CD₃OD-d₄, 300 MHz) δ 8.45 (d,J=2.4 Hz, 1H), 8.21 (s, 1H), 7.80 (dd, J=9.0, 2.4 Hz, 1H), 6.91 (dd,J=9.0, 0.6 Hz, 1H), 4.67 (dt, J=7.9, 4.0 Hz, 1H), 3.82-3.33 (m, 14H),2.41 (td, J=7.3, 2.4 Hz, 2H), 2.25 (dt, J=13.3, 6.6 Hz, 1H), 2.09-1.94(m, 1H), 1.90-1.57 (m, 4H).

Example 78:6-[4-(3-[[(2S,4S)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of ethyl3-[[(2S,4S)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoate

A solution of5-[(2S,4S)-2-(hydroxymethyl)-4-methylpyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1.1 g, 2.70 mmol, 1.00 equiv), sodium hydride (108 mg, 4.50 mmol, 1.00equiv), ethyl prop-2-enoate (2.7 g, 26.97 mmol, 10.00 equiv) in THF (25mL) was stirred for 1 h at 0° C. in an ice/salt bath. Afterconcentration, the residue was applied onto a silica gel column elutingwith EtOAc/petroleum ether (3:7) to afford 1 g (73%) of the titlecompound as a yellow oil. LCMS (ESI, m/z): 508.24 [M+H]⁺.

Step 2: Synthesis of ethyl3-[[(2S,4S)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoate

A solution of ethyl3-[[(2S,4S)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoate(1 g, 1.97 mmol, 1.00 equiv) and hydrogen chloride/dioxane (20 mL) indioxane (2 mL) was stirred overnight at 25° C. After concentration, theresidue was purified by C18 reverse phase chromatography eluting withwater/CH₃CN (65:35) to afford 530 mg (71%) of the title compound asyellow oil. LCMS (ESI, m/z): 378.16 [M+H]⁺.

Step 3: Synthesis of3-[[(2S,4S)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicAcid

A solution of ethyl3-[[(2S,4S)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoate(489 mg, 1.30 mmol, 1.00 equiv), LiOH (93 mg, 3.88 mmol, 3.00 equiv),water (25 mL) in methanol (25 mL) was stirred overnight at 25° C. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with water/CH₃CN (77:23) to afford 234 mg (52%)of the title compound as a white solid. LCMS (ESI, m/z): 350.12 [M+H]⁺.

Step 4: Synthesis of6-[4-(3-[[(2S,4S)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-[[(2S,4S)-4-methyl-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicacid (234 mg, 0.67 mmol, 1.00 equiv), DIPEA (173 mg, 1.34 mmol, 2.00equiv), HATU (254 mg, 0.67 mmol, 1.00 equiv), Int-A4 (126 mg, 0.67 mmol,1.00 equiv) in DMF (2 mL) was stirred overnight at 25° C. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with water/CH₃CN yielding the title compound(188.8 mg 54%) as a white solid. LCMS (ESI, m/z): 520.22 [M+H]⁺, ¹H NMR(Methanol-d₄, 400 MHz) δ: 8.44 (dd, J=2.3, 0.8 Hz, 1H), 8.13 (s, 1H),7.79-7.76 (dd, J=9.0, 2.3 Hz, 1H), 6.89-6.88 (dd, J=9.1, 0.9 Hz, 1H),4.67-4.60 (m, 1H), 3.83-3.65 (m, 11H), 3.48-3.44 (m, 1H), 3.37-3.35 (m,1H), 3.28 (m, 1H), 2.66-2.62 (m, 2H), 2.32-2.29 (m, 1H), 2.20-2.03 (m,1H), 1.33-1.30 (td, J=12.1, 9.0 Hz, 1H), 1.10-1.09 (d, J=6.3 Hz, 3H).

Example 79 Isomer A:6-[4-[(2Z)-4-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]but-3-enoyl]piperazin-1-yl]pyridine-3-carbonitrileand Example 79 Isomer B:6-[4-[(2Z)-4-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]but-3-enoyl]piperazin-1-yl]pyridine-3-carbonitrileand Example 79 Isomer C:6-[4-[(2E)-4-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]but-2-enoyl]piperazin-1-yl]pyridine-3-carbonitrileand Example 79 Isomer D:6-[4-[(2E)-4-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]but-2-enoyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of 2,3-dihydro-H-isoindol-1-ylmethanol Hydrochloride

A solution of tert-butyl1-(hydroxymethyl)-2,3-dihydro-1H-isoindole-2-carboxylate (1.05 g, 4.21mmol, 1.00 equiv) in hydrogen chloride/dioxane (10 mL, 4 M) was stirredfor 2 h at room temperature. The resulting solution was concentratedunder vacuum to afford 997 mg of the title compound as a pink crudesolid. LCMS (ESI, m/z): 150.08 [M+H]⁺.

Step 2: Synthesis of5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of 2,3-dihydro-1H-isoindol-1-ylmethanol hydrochloride (997mg, 5.37 mmol, 1.00 equiv), TEA (1.08 g, 10.67 mmol, 2.00 equiv) andInt-A6 (1.77 g, 5.38 mmol, 1.00 equiv) in ethanol (10 mL) was stirredfor 2 h at 60° C. and concentrated under vacuum to afford 1.3 g (55%) ofthe title compound as a pink solid. LCMS (ESI, m/z): 442.17 [M+H]⁺.

Step 3: Synthesis of methyl(2E)-4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)but-2-enoate

Under nitrogen, a solution of5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1.3 g, 2.94 mmol, 1.00 equiv), methyl (2E)-4-bromobut-2-enoate (2.61 g,14.58 mmol, 5.00 equiv), Pd₂(dba)₃ (60 mg, 0.07 mmol, 0.05 equiv),RuPhos (55 mg, 0.12 mmol, 0.10 equiv) and Cs₂CO₃ (1.91 g, 5.86 mmol,2.00 equiv) in toluene (30 mL) was stirred for 12 h at 80° C. Theresulting solution was concentrated under vacuum, and the residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(1:4) to afford 1.02 g (64%) of the title compound as a yellow solid.LCMS (ESI, m/z): 540.21 [M+H]⁺.

Step 4: Synthesis of(2E)-4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)but-2-enoicAcid

A solution of methyl(2E)-4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)but-2-enoate(1.02 g, 1.89 mmol, 1.00 equiv) and LiOH (397 mg, 16.58 mmol, 5.00equiv) in THF (10 mL) and water (2 mL) was stirred for 1 h at roomtemperature. The resulting solution was diluted with 3 mL of water, andthe pH value of the solution was adjusted to 4 with hydrogen chloride (1M). The resulting solution was filtered and the solid was collected toafford 832 mg (84%) of the title compound as a yellow solid. LCMS (ESI,m/z): 525.19 [M+H]⁺.

Step 5: Synthesis of(2E)-1-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)but-2-enoicAcid

A solution of(2E)-4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)but-2-enoicacid (110 mg, 0.21 mmol, 1.00 equiv) and TFA (1 mL) in DCM (5 mL) wasstirred for 1 h at room temperature, and the resulting solution wasconcentrated under vacuum to afford 100 mg of the title compound ascrude brown oil. LCMS (ESI, m/z): 396.11 [M+H]⁺.

Step 6: Synthesis of6-[4-[(2Z)-4-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]but-2-enoyl]piperazin-1-yl]pyridine-3-carbonitrile,6-[4-[(2Z)-4-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1yl]methoxy]but-2-enoyl]piperazin-1-yl]pyridine-3-carbonitrile,6-[4-[(2E)-4-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]but-2-enoyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(2E)-4-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]but-2-enoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of(2E)-4-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)but-2-enoicacid (500 mg, 1.27 mmol, 1.00 equiv), Int-A4 (239 mg, 1.27 mmol, 1.00equiv), HATU (386 mg, 1.01 mmol, 0.8 equiv) and DIPEA (492 mg, 3.81mmol, 3.0 equiv) in DMF (5 mL) was stirred for 2h at room temperature,The resulting solution was purified by reverse phase chromatographyeluting with water/CH₃CN. After concentration, the residue was furtherpurified by Prep-HPLC and Chiral-Prep-HPLC (Chiralpak Cellulose-SB,0.46*15 cm; 3 um, MtBE (0.1% DEA):EtOH=80:20, 1.0 mL/min) yielding thetitle compounds as white solids. The absolute stereochemistry wasassigned based on a protein X-ray crystal structure obtained of Example18b which confirmed (S)-absolute stereochemistry and was observed to bethe more potent enantiomer (see Table A-1).

Example 79 Isomer A

4.3 mg, 0.60%, LCMS (ESI, m/z): 566.10 [M+H]⁺, ¹H NMR (DMSO-d₆, 300MHz): δ12.59 (s, 1H), 8.53 (dd, J=2.4, 0.7 Hz, 1H), 8.26 (s, 1H), 7.93(dd, J=9.1, 2.4 Hz, 1H), 7.51-7.29 (m, 4H), 6.94 (d, J=9.1 Hz, 1H), 6.17(d, J=6.0 Hz, 1H), 6.07 (d, J=3.6 Hz, 1H), 5.13 (d, J=14.7 Hz, 1H),4.56-4.46 (m, 2H), 4.27 (dd, J=10.8, 3.0 Hz, 1H), 3.96 (dd, J=11.0, 6.7Hz, 1H), 3.80-3.35 (m, 8H), 2.84 (dd, J=6.8, 1.7 Hz, 2H). tR=4.876 min.

Example 79 Isomer B

3.4 mg, 0.37%, LCMS (ESI, m/z): 566.10[M+H]⁺, 1H NMR (DMSO-d₆, 300 MHz):δ12.58 (s, 1H), 8.53 (d, J=2.3 Hz, 1H), 8.26 (s, 1H), 7.92 (dd, J=9.1,2.4 Hz, 1H), 7.56-7.27 (m, 4H), 6.94 (d, J=9.1 Hz, 1H), 6.16 (d, J=6.0Hz, 1H), 6.06 (s, 1H), 5.13 (d, J=14.8 Hz, 1H), 4.61-4.42 (m, 2H), 4.26(dd, J=11.0, 3.1 Hz, 1H), 3.97 (dd, J=11.0, 6.6 Hz, 1H), 3.74-3.33 (m,8H), 2.83 (dd, J=6.8, 1.7 Hz, 2H). tR=9.413 min.

Example 79 Isomer C

10.3 mg, 1.44%, LCMS (ESI, m/z): 566.10[M+H]⁺, ¹H NMR (DMSO-d₆, 300 MHz)δ12.58 (s, 1H), 8.53 (dd, J=2.3, 0.7 Hz, 1H), 8.32 (s, 1H), 7.94 (dd,J=9.1, 2.4 Hz, 1H), 7.50-7.25 (m, 4H), 6.98 (d, J=9.1 Hz, 1H), 6.69 (dt,J=15.1, 3.9 Hz, 1H), 6.39 (d, J=15.1 Hz, 1H), 6.06 (s, 1H), 5.12 (d,J=14.7 Hz, 1H), 4.58 (d, J=14.8 Hz, 1H), 4.19 (m, 2H), 3.92 (dd, J=10.0,3.4 Hz, 1H), 3.78-3.45 (m, 9H). tR=6.804 min.

Example 79 Isomer D

6.3 mg, 0.88%, ¹H NMR (CD₃OD, 400 MHz) δ8.50-8.42 (m, 2H), 7.79 (dd,J=9.1, 2.4 Hz, 1H), 7.50-7.29 (m, 4H), 6.92 (dd, J=9.1, 0.9 Hz, 1H),6.83 (dt, J=15.2, 3.7 Hz, 1H), 6.45 (dt, J=15.1, 2.2 Hz, 1H), 6.07 (d,J=6.4 Hz, 1H), 5.27 (d, J=14.8 Hz, 1H), 4.65 (d, J=15.2 Hz, 1H), 4.27(m, 1H), 4.18 (m, 1H), 4.04 (dd, J=9.9, 3.4 Hz, 1H), 3.82-3.56 (m, 9H).tR=8.206 min.

Example 80 Isomer A:2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]-N-[(1r,4r)-4-[(pyridin-2-yl)amino]cyclohexyl]acetamideand Example 80 Isomer B:2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]-N-[(1s,4s)-4-[(pyridin-2-yl)amino]cyclohexyl]acetamide

Step 1: Synthesis of Tert-ButylN-[4-[(pyridin-2-yl)amino]cyclohexyl]carbamate

Under nitrogen, a solution of tert-butyl N-(4-aminocyclohexyl)carbamate(1 g, 4.67 mmol, 2.50 equiv), Pd₂(dba)₃CHCl₃ (196 mg, 0.10 equiv),Xantphos, Cs₂CO₃ (2.19 g, 2.0 equiv), 2-chloropyridine (212 mg, 1.87mmol, 1.00 equiv) in dioxane (10 mL) was stirred for 12 h at 80° C. inan oil bath. The residue was applied onto a silica gel column withEtOAc/petroleum ether (1:4) to afford 330 mg (61%) of the title compoundas a solid. LCMS (ESI, m/z): 292.19 [M+H]⁺

Step 2: Synthesis of 1-N-(pyridin-2-yl)cyclohexane-1,4-diamineHydrochloride

A solution of tert-butyl N-[4-[(pyridin-2-yl)amino]cyclohexyl]carbamate(330 mg, 1.13 mmol, 1.00 equiv), hydrogen chloride/dioxane (15 mL) wasstirred for 2 h at room temperature. The resulting mixture wasconcentrated under vacuum. This resulted in 220 mg (crude) of the titlecompound as a solid. LCMS (ESI, m/z): 192.14 [M−Cl]⁺.

Step 3: Synthesis of2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]-N-[(1r,4r)-4-[(pyridin-2-yl)amino]cyclohexyl]acetamideand2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]-N-[(1s,4s)-4-[(pyridin-2-yl)amino]cyclohexyl]acetamide

A solution of 1-N-(pyridin-2-yl)cyclohexane-1,4-diamine hydrochloride(124 mg, 0.54 mmol, 1.00 equiv), HATU (178 mg, 0.47 mmol, 1.00 equiv),DIPEA (243 mg, 1.88 mmol, 4.00 equiv), DMF (2 mL),2-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxyaceticacid (150 mg, 0.47 mmol, 1.00 equiv) was stirred for 2 h at roomtemperature. The crude product was purified by C18 reverse phasechromatography eluting with water/CH₃CN yielding (after arbitraryassignment of the stereochemistry) the title compounds as white solids.

Example 80 Isomer A

2.5 mg, 1%, LCMS (ESI, m/z): 495.23 [M+H]⁺, ¹HNMR (DMSO-d₆, 300 MHz) δ:12.41 (s, 1H), 8.11 (s, 1H), 7.92 (dd, J=5.1, 1.9 Hz, 1H), 7.31 (ddd,J=8.7, 7.0, 2.0 Hz, 1H), 7.21 (d, J=7.4 Hz, 1H), 6.50 (d, J=8.4 Hz, 1H),6.41 (ddd, J=7.1, 5.0, 1.0 Hz, 1H), 6.16 (d, J=6.6 Hz, 1H), 4.60 (dr,1H), 3.86 (s, 2H), 3.79 (dr, 1H), 3.69 (dr, 1H), 3.60-3.50 (m, 2H),3.28-3.10 (m, 2H), 2.10 (dr, 1H), 1.89 (dr, 1H), 1.63-1.55 (m, 10H).

Example 80 Isomer B

4.3 mg, 2%, LCMS (ESI, m/z): 495.23 [M+H]⁺, ¹HNMR (DMSO-d₆, 300 MHz) δ:12.42 (s, 1H), 8.12 (d, J=1.5 Hz, 1H), 7.91 (dd, J=5.5, 2.0 Hz, 1H),7.30 (ddd, J=8.7, 7.1, 2.0 Hz, 1H), 7.16 (d, J=8.2 Hz, 1H), 6.45-6.35(m, 2H), 6.31 (d, J=7.6 Hz, 1H), 4.61 (dr, 1H), 3.83 (d, J=2.7 Hz, 2H),3.58-3.47 (m, 5H), 3.26-3.20 (m, 1H), 2.10 (drs, 1H), 1.97-1.91 (m, 3H),1.89-1.73 (m, 4H), 1.30-1.22 (m, 4H).

Example 81 Isomer A:3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]-N-[(1r,4r)-4-[(pyridin-2-yl)amino]cyclohexyl]propanamideand Example 81 Isomer B:3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]-N-[(1s,4s)-4-[(pyridin-2-yl)amino]cyclohexyl]propanamide

Step 1: Synthesis of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]-N-[(1r,4r)-4-[(pyridin-2-yl)amino]cyclohexyl]propanamideand3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]-N-[(1s,4s)-4-[(pyridin-2-yl)amino]cyclohexyl]propanamide

A solution of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicacid (75 mg, 0.22 mmol, 1 equiv), DIPEA (115.6 mg, 0.89 mmol, 4.00equiv), HATU (85.1 mg, 0.22 mmol, 1 equiv),N1-(pyridin-2-yl)cyclohexane-1,4-diamine dihydrochloride (118.2 mg, 0.45mmol, 2.00 equiv) in DMF (2 mL) was stirred for 2 h at room temperature.The crude product was purified by Prep-HPLC yielding (after arbitraryassignment of the stereochemistry) the title compounds as white solids.

Example 81 Isomer A

3.0 mg 2.42%, LCMS (ESI, m/z): 632.22 [M+H]⁺, ¹H NMR (DMSO-d₆, 300 MHz)δ: 12.35 (s, 1H), 8.15 (s, 1H), 8.00 (s, 1H), 7.95 (d, J=3.6 Hz, 1H),7.70 (d, J=7.7 Hz, 1H), 7.35-7.29 (m, 1H), 6.51-6.39 (m, 2H), 6.25 (d,J=7.8 Hz, 1H), 4.50 (dr, 1H), 3.74-3.52 (m, 7H), 3.20 (dr, 1H),2.30-2.26 (m, 2H), 2.07-1.91 (m, 1H), 1.87 (d, J=18.5 Hz, 1H), 1.71-1.56(m, 10H).

Example 81 Isomer B

4.9 mg 3.95%, LCMS (ESI, m/z): 632.22 [M+H]⁺, ¹H NMR (DMSO-d⁶, 300 MHz)δ: 12.37 (s, 1H), 8.31 (s, 1H), 8.00 (s, 1H), 7.95 (d, J=3.6 Hz, 1H),7.72 (d, J=7.2 Hz, 1H), 7.34-7.28 (m, 1H), 6.42-6.38 (m, 2H), 6.27 (d,J=6.5 Hz, 1H), 4.50 (dr, 1H), 3.61-3.50 (m, 7H), 3.23 (dr, 1H),2.27-2.25 (m, 2H), 2.07-1.95 (m, 1H), 1.87-1.62 (m, 7H), 1.23-1.16 (m,4H).

Example 82 Isomer A:6-[4-(1S,4r)-[(4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydro-pyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrileand Example 82 Isomer B:6-[4-(1R,4s)-[(4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexyl)-carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl(2S)-2-[4-(ethoxycarbonyl)phenoxymethyl]pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1 g, 4.97 mmol, 1.00equiv) in THF (20 mL), ethyl 4-hydroxybenzoate (1.2 g, 7.22 mmol, 1.45equiv), and PPh₃ (2 g, 7.63 mmol, 1.53 equiv) were added at 0° C. Thiswas followed by the addition of DEAD (1.2 mL) dropwise. The resultingsolution was stirred for 5 h at room temperature. The reaction was thenquenched by the addition of 20 mL of water. The resulting solution wasdiluted with 250 mL of EtOAc and washed with 50 mL of NH₄Cl and 50 mL ofbrine. The organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with EtOAc/petroleum ether (1:4). This resulted in 1.5 g (86%) ofthe title compound as a solid. LCMS (ESI, m/z): 350.20 [M+H]⁺.

Step 2: Synthesis of Tert-Butyl(2S)-2-([[4-(ethoxycarbonyl)cyclohexyl]oxy]methyl)pyrrolidine-1-carboxylate

A solution of tert-butyl(2S)-2-[4-(ethoxycarbonyl)phenoxymethyl]pyrrolidine-1-carboxylate (1.4g, 4.01 mmol, 1.00 equiv) and Rh/Al₂O₃ (2 g) in ethanol (80 mL) and AcOH(4 mL) was stirred for 5 h at room temperature under hydrogen. Thesolids were filtered out. The resulting mixture was concentrated undervacuum. The resulting solution was diluted with 250 mL of EtOAc. Theresulting mixture was washed with 2×50 mL of sodium bicarbonate, 50 mLof NH₄Cl and 50 mL of brine. The organic layer was dried over anhydroussodium sulfate and concentrated under vacuum. This resulted in 1.25 g(crude) of the title compound as oil. LCMS (ESI, m/z): 356.24 [M+H]⁺.

Step 3: Synthesis of ethyl4-[(2S)-pyrrolidin-2-ylmethoxy]cyclohexane-1-carboxylate hydrochloride

A solution of tert-butyl(2S)-2-([[4-(ethoxycarbonyl)cyclohexyl]oxy]methyl)pyrrolidine-1-carboxylate(1.25 g, 3.52 mmol, 1.00 equiv) in hydrogen chloride/dioxane (15 mL) wasstirred for 1 h at room temperature. The resulting mixture wasconcentrated under vacuum. This resulted in 900 mg (crude) of the titlecompound as oil. LCMS (ESI, m/z): 256.19 [M+H]⁺.

Step 4: Synthesis of ethyl4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexane-1-carboxylate

A solution of ethyl4-[(2S)-pyrrolidin-2-ylmethoxy]cyclohexane-1-carboxylate hydrochloride(900 mg, 3.08 mmol, 1.00 equiv), Int-A6 (1.15 g, 3.50 mmol, 1.13 equiv)and TEA (2 mL) in ethanol (15 mL) was stirred for 1 h at 60° C. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with EtOAc/petroleum ether (1:3). This resultedin 1.2 g (71%) of the title compound as colorless oil. LCMS (ESI, m/z):548.28 [M+H]⁺.

Step 5: Synthesis of4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexane-1-carboxylicAcid

To a stirred solution of ethyl4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexane-1-carboxylate(550 mg, 1.00 mmol, 1.00 equiv) in THF (12 mL) and water (4 mL),LiOH-water (200 mg, 8.35 mmol, 8.32 equiv) was added at 0° C. Theresulting solution was stirred overnight at room temperature. The pHvalue of the solution was adjusted to 1 with hydrogen chloride (1 M).The resulting solution was diluted with 250 mL of EtOAc. The resultingmixture was washed with 50 mL of brine. The organic layer was dried overanhydrous sodium sulfate and concentrated under vacuum. This resulted in550 mg (crude) of the title compound as a solid. LCMS (ESI, m/z): 520.24[M+H]⁺.

Step 6: Synthesis of4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexane-1-carboxylicacid as a solid

A solution of4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydro-pyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexane-1-carboxylicacid (550 mg, 1.06 mmol, 1.00 equiv) in hydrogen chloride/dioxane (10mL) was stirred overnight at room temperature. The resulting mixture wasconcentrated under vacuum. The crude product was purified by C18 reversephase chromatography eluting with water/CH₃CN. This resulted in 170 mg(41%) of the title compound as a solid. LCMS (ESI, m/z): 390.16 [M+H]⁺.

Step 7: Synthesis of6-[4-(1S,4r)-[(4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-(1R,4s)-[(4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

To a stirred solution of4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclohexane-1-carboxylicacid (175 mg, 0.45 mmol, 1.00 equiv) in DMF (5 mL), were added Int-A4(90 mg, 0.48 mmol, 1.06 equiv), DIPEA (0.5 mL) and HATU (200 mg, 0.53mmol, 1.17 equiv). The resulting solution was stirred overnight at roomtemperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with water/CH₃CN. The residue wasfurther purified by Prep-HPLC yielding (after arbitrary assignment ofstereoisomers) the title compounds as white solids.

Example 82 Isomer A

70.2 mg, 28%, LCMS (ESI, m/z): 560.15 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 12.30 (s, 1H), 8.51 (dd, J=2.3, 0.6 Hz, 1H), 8.07 (s, 1H), 7.88 (dd,J=9.1, 2.4 Hz, 1H), 6.98-6.88 (m, 1H), 4.64-4.53 (m, 1H), 3.77-3.42 (m,11H), 3.31-3.17 (m, 2H), 2.67-2.54 (m, 1H), 2.16-2.09 (m, 1H), 1.96-1.87(m, 1H), 1.83-1.73 (m, 1H), 1.72-1.49 (m, 5H), 1.48-1.31 (m, 4H).

Example 82 Isomer B

1.8 mg, 0.7%, LCMS (ESI, m/z): 560.30 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 12.32 (s, 1H), 8.51 (d, J=2.3 Hz, 1H), 8.05 (s, 1H), 7.88 (dd, J=9.1,2.4 Hz, 1H), 6.93 (d, J=9.1 Hz, 1H), 4.61-4.49 (m, 1H), 3.78-3.45 (m,10H), 3.28-3.09 (m, 3H), 2.62-2.53 (m, 1H), 2.17-2.02 (m, 1H), 1.99-1.79(m, 3H), 1.73-1.54 (m, 4H), 1.42-1.25 (m, 2H), 1.21-1.03 (m, 2H).

Example 83:2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]-N-[4-(pyridin-2-yloxy)cyclohexyl]acetamide

Step 1: Synthesis of Tert-ButylN-[4-(pyridin-2-yloxy)cyclohexyl]carbamate

Under nitrogen, a solution of tert-butylN-(4-hydroxycyclohexyl)carbamate (1.2 g, 5.57 mmol, 1.00 equiv),pyridin-2-ol (795 mg, 8.36 mmol, 1.50 equiv), PPh₃ (2.19 g, 8.35 mmol,1.50 equiv), and DIAD (1.69 g, 8.36 mmol, 1.50 equiv) in THF (10 mL) wasstirred for 3 h at 25° C. After concentration, the residue was appliedonto a silica gel column eluting with EtOAc/petroleum ether (15:85) toafford 650 mg (40%) of the title compound as a colorless solid. LCMS(ESI, m/z): 293.18 [M+H]⁺.

Step 2: Synthesis of 4-(pyridin-2-yloxy)cyclohexan-1-amine

A solution of tert-butyl N-[4-(pyridin-2-yloxy)cyclohexyl]carbamate (650mg, 2.22 mmol, 1.00 equiv) in hydrogen chloride/dioxane (20 mL) wasstirred for 0.5 h at 25° C. After concentration, the reaction mixturewas adjusted to pH 7-8 with aqueous NaHCO₃. The resulting solution wasextracted with DCM (5×40 mL), and the organic layers were combined anddried over anhydrous sodium sulfate and concentrated under vacuum toafford 300 mg (59%) of the title compound as a white solid. LCMS (ESI,m/z): 193.13 [M+H]⁺.

Step 3: Synthesis of2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]-N-[4-(pyridin-2-yloxy)cyclohexyl]acetamide

A solution of2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]aceticacid (200 mg, 0.62 mmol, 1.00 equiv), DIPEA (161 mg, 1.25 mmol, 2.00equiv), HATU (237 mg, 0.62 mmol, 1.00 equiv),4-(pyridin-2-yloxy)cyclohexan-1-amine (142 mg, 0.62 mmol, 1.00 equiv) inDMF (2 mL) was stirred for 1 h at 25° C. After concentration, theresidue was purified by C18 reverse phase chromatography eluting withwater/CH₃CN yielding the title compound (88.5 mg 29%) as a white solid.LCMS (ESI, m/z): 496.21 [M+H]⁺, ¹H NMR (Methanol-d₄, 400 MHz) δ: 8.26(s, 1H), 8.12 (d, J=1.6 Hz, 1H), 7.71-7.67 (m, 1H), 6.95-6.92 (m, 1H),6.87-6.85 (m, 1H), 5.14 (s, 1H), 4.72 (s, 1H), 4.01-3.92 (m, 2H),3.85-3.74 (dr, 1H), 3.70-3.72 (m, 2H), 3.54-3.50 (m, 1H), 3.41 (m, 1H),2.28 (s, 1H), 2.05-2.01 (m 3H), 1.76-1.67 (m, 8H).

Example 84:3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]-N-[4-(pyridin-2-yloxy)cyclohexyl]propanamide

Step 1: Synthesis of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]-N-[4-(pyridin-2-yloxy)cyclohexyl]propanamide

A solution of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicacid (140 mg, 0.42 mmol, 1.00 equiv), DIPEA (108 mg, 0.84 mmol, 2.00equiv), HATU (159 mg, 0.42 mmol, 1.00 equiv), and4-(pyridin-2-yloxy)cyclohexan-1-amine hydrochloride (95 mg, 0.42 mmol,1.00 equiv) in DMF (2 mL) was stirred for 40 min at 25° C. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with water/CH₃CN and was purified by Prep-HPLCyielding the title compound (46.3 mg 22%) as a white solid. LCMS (ESI,m/z): 510.22 [M+H]⁺, ¹H NMR (Methanol-d₄, 400 MHz) δ: 8.12-8.10 (m, 2H),7.70-7.66 (m, 1H), 6.95-6.88 (m, 1H), 6.80 (dt, J=8.5, 0.9 Hz, 1H), 5.13(s, 1H), 4.50 (m, 1H), 3.77-3.60 (m, 5H), 3.48-3.44 (m, 1H), 3.35-3.40(m, 1H), 2.39 (t, J=6.1 Hz, 2H), 2.23 (d, J=6.9 Hz, 1H), 2.02 (dr, 3H),1.72 (m, 8H).

Example 85:3-[(5-cyanopyridin-2-yl)amino]-N-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)propanamide

Step 1: Synthesis of5-[(2S)-2-(3-nitrophenoxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(500 mg, 1.27 mmol, 1.00 equiv), [Pd(allyl)Cl]₂ (50 mg, 0.14 mmol, 0.10equiv), Rockphos (120 mg, 0.26 mmol, 0.20 equiv), 1-bromo-3-nitrobenzene(310 mg, 1.53 mmol, 1.20 equiv) and Cs₂CO₃ (830 mg, 2.55 mmol, 2.00equiv) in toluene (10 mL) was stirred for 16 h at 80° C. The solid wasfiltered out and the resulting solution was concentrated under vacuum.The residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1:1) to afford 364 mg (56%) of the title compoundas light brown oil. LCMS (ESI, m/z): 515.19[M+H]⁺.

Step 2: Synthesis of5-[(2S)-2-(3-aminophenoxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Under an atmosphere of hydrogen, a solution of5-[(2S)-2-(3-aminophenoxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(255 mg, 0.53 mmol, 1.00 equiv) and Pd/C (25 mg) in MeOH (10 mL) wasstirred for 3 h at room temperature. The solids were filtered out andthe resulting solution was concentrated under vacuum to afford 45 mg(24%) of the title compound as a brown solid. LCMS(ESI, m/z): 485.22[M+H]⁺.

Step 3: Synthesis of3-[(5-cyanopyridin-2-yl)amino]-N-[3-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy)phenyl]propanamide

A solution of 3-[(5-cyanopyridin-2-yl)amino]propanoic acid (62 mg, 0.32mmol, 1.20 equiv), EDC.HCl (104 mg, 0.67 mmol, 2.00 equiv), DMAP (66 mg,0.54 mmol, 2.00 equiv) and5-[(2S)-2-(3-aminophenoxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(131 mg, 0.27 mmol, 1.00 equiv) in DMF (5 mL) was stirred for 8 h atroom temperature. The resulting solution was diluted with 20 ml ofwater, extracted with 3×50 ml of EtOAc, and the organic layers werecombined, washed with 50 ml of brine and concentrated under vacuum. Theresidue was purified by C18 reverse phase chromatography eluting withwater/CH₃CN to afford 60 mg (34%) of the title compound as a brownsolid. LCMS (ESI, m/z): 658.27[M+H]⁺.

Step 4: Synthesis of3-[(5-cyanopyridin-2-yl)amino]-N-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)propanamide

A solution of3-[(5-cyanopyridin-2-yl)amino]-N-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)propanamide(300 mg, 0.46 mmol, 1.00 equiv) and TFA (2 mL) in DCM (10 mL) wasstirred for 2 h at room temperature. The resulting solution wasconcentrated under vacuum and the residue was purified by C18 reversephase chromatography eluting with water/CH₃CN. After concentration theresidue was further purified by Prep-HPLC yielding the title compound(28.5 mg, 12.00%) as a white solid. LCMS (ESI, m/z): 528.15[M+H]+, ¹HNMR (CD3OD, 300 MHz) δ 8.33 (d, J=2.2 Hz, 1H), 8.22 (s, 1H), 7.60 (dd,J=9.0, 2.1 Hz, 1H), 7.28 (t, J=2.1 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 7.04(d, J=8.1 Hz, 1H), 6.64-6.56 (m, 2H), 4.89-4.82 (m, 1H), 4.19 (dd,J=10.2, 3.9 Hz, 1H), 4.01 (dd, J=10.2, 6.9 Hz, 1H), 3.76 (t, J=6.3 Hz,3H), 3.45-3.39 (m, 1H), 2.67 (t, J=6.6 Hz, 2H), 2.36 (d, J=10.8 Hz, 1H),2.06 (dd, J=10.2, 5.9 Hz, 1H), 1.92-1.79 (m, 2H).

Example 86:N-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)prop-2-enamide

Step 1: Synthesis ofN-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)prop-2-enamide

To a solution of5-[(2S)-2-(3-aminophenoxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(150 mg, 0.31 mmol, 1.00 equiv) and TEA (93 mg, 0.92 mmol, 2.00 equiv)in DCM (2.5 mL) was added prop-2-enoyl chloride (31 mg, 0.34 mmol, 1.10equiv). The resulting solution was stirred for 1 h at room temperature,quenched with 10 ml of water and extracted with 3×15 ml of EtOAc. Theorganic layers were combined, washed with 10 ml of brine andconcentrated under vacuum. The residue was purified by C18 reverse phasechromatography eluting with water/CH₃CN to afford 21 mg (13%) of thetitle compound as a brown solid. LCMS (ESI, m/z): 539.23 [M+H]⁺.

Step 2: Synthesis ofN-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)prop-2-enamide

A solution ofN-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)prop-2-enamide(279 mg, 0.52 mmol, 1.00 equiv) and TFA (1 mL) in DCM (5 mL) was stirredfor 3 h at room temperature. The resulting solution was concentratedunder vacuum and the residue was purified by C18 reverse phasechromatography eluting with water/CH₃CN. After concentration, theresidue was further purified by Prep-HPLC yielding the title compound11.1 mg (5.01%) as a white solid. LCMS (ESI, m/z): 409.15 [M+H]⁺, ¹HNMR(DMSO-d₆, 300 MHz) δ 12.35 (s, 1H), 10.14 (s, 1H), 8.16 (s, 1H), 7.30(s, 1H), 7.21 (d, J=5.1 Hz, 2H), 6.63 (td, J=4.5, 2.5 Hz, 1H), 6.45 (dd,J=17.0, 10.0 Hz, 1H), 6.27 (dd, J=17.0, 2.1 Hz, 1H), 5.77 (dd, J=9.9,2.1 Hz, 1H), 4.83 (s, 1H), 4.07 (dd, J=10.2, 4.2 Hz, 1H), 3.94 (dd,J=10.2, 6.3 Hz, 1H), 3.62 (s, 1H), 3.28-3.20 (m, 1H), 2.23 (dd, J=13.0,6.9 Hz, 1H), 1.98-1.90 (m, 1H), 1.86-1.67 (m, 2H).

Example 87:3-[(5-cyanopyridin-2-yl)amino]-N-(5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridin-3-yl)propanamide

Step 1: Synthesis of5-[(2S)-2-[[(5-nitropyridin-3-yl)oxy]methyl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1 g, 2.54 mmol, 1.00 equiv), [Pd(allyl)Cl]₂ (92.96 mg, 0.10 equiv),Rockphos (119.03 mg, 0.10 equiv), Cs₂CO₃ (2.48 g, 7.61 mmol, 3.00equiv), 3-bromo-5-nitropyridine (1.026 g, 5.05 mmol, 2.00 equiv) intoluene (20 mL) was stirred for 5 h at 80° C. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (1:1) to afford 600 mg (46%)of the title compound as brown oil. LCMS (ESI, m/z): 516.19 [M+H]⁺.

Step 2: Synthesis of5-[(2S)-2-[[(5-aminopyridin-3-yl)oxy]methyl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[(2S)-2-[[(5-nitropyridin-3-yl)oxy]methyl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(467 mg, 0.91 mmol, 1.00 equiv), Fe (253.9 mg, 5.00 equiv) in aceticacid (5 mL) was stirred for 15 h at 70° C. After concentration, theresidue was purified by C18 reverse phase chromatography eluting withwater/CH₃CN to afford 400 mg (91%) of the title compound as a brownsolid. LCMS (ESI, m/z): 486.22[M+H]⁺.

Step 3: Synthesis of3-[(5-cyanopyridin-2-yl)amino]-N-(5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridin-3-yl)propanamide

A solution of5-[(2S)-2-[[(5-aminopyridin-3-yl)oxy]methyl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(364 mg, 0.75 mmol, 1.00 equiv), EDC.HCl (360.5 mg, 1.88 mmol, 2.50equiv), 4-dimethylaminopyridine (274.87 mg, 2.25 mmol, 3.00 equiv),3-[(5-cyanopyridin-2-yl)amino]propanoic acid (172 mg, 0.90 mmol, 1.20equiv) in DMF (4 mL) was stirred for 3 h at 60° C. The resultingsolution was quenched with 40 ml water and extracted with 4×50 mL ofEtOAc. The organic layers were combined. After the resulting mixture wasconcentrated under vacuum, the residue was applied onto a silica gelcolumn with MeOH/CH₂Cl₂ (1:10) to afford 350 mg (71%) of the titlecompound as a brown solid. LCMS (ESI, m/z): 659.28[M+H]⁺.

Step 4: Synthesis of3-[(5-cyanopyridin-2-yl)amino]-N-(5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridin-3-yl)propanamide

A solution of3-[(5-cyanopyridin-2-yl)amino]-N-(5-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyridin-3-yl)propanamide(134 mg, 0.20 mmol, 1.00 equiv), trifluoroacetic acid (1 mL) in DCM (5mL) was stirred for 1 h at room temperature. After concentration, theresidue was purified by Prep-HPLC yielding the title compound (39.1 mg,36%) as a white solid. LCMS (ESI, m/z): 529.25 [M+H]⁺, ¹HNMR (300 MHz,Methanol-d4) δ 8.33 (d, J=2.3 Hz, 1H), 8.29 (dd, J=2.3, 1.8 Hz, 2H),7.93 (d, J=2.6 Hz, 1H), 7.85 (d, J=2.3 Hz, 1H), 7.59 (dd, J=8.9, 2.3 Hz,1H), 6.59 (d, J=9.0 Hz, 1H), 4.87 (s, 1H) 4.30 (d, J=10.3 Hz, 1H), 4.11(d, J=10.3 Hz, 1H), 3.77 (dd, J=6.6, 7.5 Hz, 3H), 3.55-3.36 (m, 1H),2.87-2.58 (m, 2H), 2.39-2.31 (m, 1H), 2.11-2.04 (m, 1H), 2.04-1.67 (m,2H).

Example 88:(S)-6-(4-(2-(2-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)ethoxy)acetyl)piperazin-1-yl)nicotinonitrile

Step 1: Synthesis of (S)-tert-butyl2-(2-hydroxyethyl)pyrrolidine-1-carboxylate

A solution of 2-[(2S)-1-[(tert-butoxy)carbonyl]pyrrolidin-2-yl]aceticacid (460 mg, 2.01 mmol, 1.00 equiv), BH₃/Me₂S (2 mL) in THF (8 mL) wasstirred for 2 h at 80° C. The resulting solution was quenched with MeOH.After concentrating under vacuum, the residue was applied onto a silicagel column eluting with EtOAc/petroleum ether (1:1) to afford 210 mg(49%) of the title compound as white oil. LCMS (ESI, m/z): 216.15[M+H]⁺.

Step 2: Synthesis of (S)-2-(pyrrolidin-2-yl)ethanol Hydrochloride

A solution of (S)-tert-butyl 2-(2-hydroxyethyl)pyrrolidine-1-carboxylate(210 mg, 1.00 mmol, 1.00 equiv) in hydrogen chloride/dioxane (5 mL) wasstirred for 1 h at room temperature. The resulting mixture wasconcentrated under vacuum to afford 150 mg crude of the title compound.LCMS (ESI, m/z): 116.10 [M+H]⁺.

Step 3: Synthesis of(S)-5-(2-(2-hydroxyethyl)pyrrolidin-1-yl)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one

A solution of Int-A6 (360 mg, 1.09 mmol, 1.10 equiv),(S)-2-(pyrrolidin-2-yl)ethanol hydrochloride (150 mg, 0.99 mmol, 1.00equiv), TEA (1 mL) in ethanol (10 mL) was stirred for 1 h at 60° C.After concentration, the residue was applied onto a silica gel columneluting with EtOAc/petroleum ether (1:1) to afford 250 mg (62%) of thetitle compound as a white solid. LCMS (ESI, m/z): 408.20 [M+H]⁺.

Step 4: Synthesis of(S)-6-(4-(2-(2-(1-(6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)ethoxy)acetyl)piperazin-1-yl)nicotinonitrile

A solution of(S)-5-(2-(2-hydroxyethyl)pyrrolidin-1-yl)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one(200 mg, 0.49 mmol, 1.00 equiv),6-[4-(2-chloroacetyl)piperazin-1-yl]pyridine-3-carbonitrile (132 mg,0.50 mmol, 1.00 equiv), sodium hydride (30 mg, 1.25 mmol, 1.50 equiv) inDMF (5 mL) was stirred for 2 h at room temperature. The resultingsolution was quenched with water and extracted with EtOAc (3×50 mL), andthe organic layers were combined. The solution was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column eluting with EtOAc/petroleum ether (1:10) toafford 80 mg (26%) of the title compound as a white solid. LCMS (ESI,m/z): 636.29 [M+H]⁺.

Step 5: Synthesis of(S)-6-(4-(2-(2-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)ethoxy)acetyl)piperazin-1-yl)nicotinonitrile

A solution of(S)-6-(4-(2-(2-(1-(6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)ethoxy)acetyl)piperazin-1-yl)nicotinonitrile(80 mg, 0.13 mmol, 1.00 equiv) in hydrogen chloride/dioxane (10 mL) wasstirred for 2 h at room temperature. After concentration, the residuewas purified by C18 reverse phase chromatography eluting withwater/CH₃CN yielding the title compound (12.6 mg, 20%) as a white solid.LCMS (ESI, m/z): 506.15 [M+H]⁺, ¹HNMR (Methanol-d₄, 300 MHz) δ: 8.45 (d,J=2.4 Hz, 1H), 8.08 (s, 1H), 7.78 (dd, J=9.1, 2.4 Hz, 1H), 6.90 (dd,J=9.1, 0.8 Hz, 1H), 4.55-4.48 (m, 1H), 4.30 (s, 2H), 3.85-3.63 (m, 11H),3.41-3.32 (m, 1H), 2.39 (t, J=5.4 Hz, 1H), 2.24-2.07 (m, 1H), 2.03-1.95(m, 1H), 1.87-1.73 (m, 3H).

Example 89:6-[4-[2-([2-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]ethyl]amino)acetyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of5-[(2S)-2-(2-azidoethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[(2S)-2-(2-hydroxyethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1.2 g, 2.94 mmol, 1.00 equiv), DPPA (1.32 g, 4.80 mmol, 1.60 equiv),DBU (730 mg, 4.80 mmol, 1.60 equiv) in toluene (10 mL) was stirred for 3h at 60° C. The solvent was concentrated under vacuum and the residuewas applied onto a silica gel column eluting with EtOAc/petroleum ether(1:1) to afford 1 g (79%) of the title compound as a white solid. LCMS(ESI, m/z): 433.20 [M+H]+.

Step 2: Synthesis of5-[(2S)-2-(2-aminoethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[(2S)-2-(2-azidoethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(864 mg, 2.00 mmol, 1.00 equiv), and Pd/C (100 mg) in methanol (10 mL)was stirred for 2 h at room temperature under H₂ atmosphere. After thesolids were filtered out, the resulting mixture was concentrated undervacuum to afford 700 mg crude of the title compound as white oil. LCMS(ESI, m/z): 407.21 [M+H]+.

Step 3: Synthesis of Tert-ButylN-[2-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]ethyl]carbamate

A solution of5-[(2S)-2-(2-aminoethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(406 mg, 1.00 mmol, 1.00 equiv), (Boc)₂O (218 mg, 1.00 mmol, 1.00 equiv)in ethanol (5 mL) was stirred for 2 h at 100° C. After concentration,the residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1:1) to afford 380 mg (75%) of the title compoundas a white solid. LCMS (ESI, m/z): 507.26 [M+H]+.

Step 4: Synthesis of Tert-ButylN-[2-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-2-oxoethyl]-N-[2-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]ethyl]carbamate

A solution of6-[4-(2-chloroacetyl)piperazin-1-yl]pyridine-3-carbonitrile (158 mg, 0.6mmol, 1.00 equiv), tert-butylN-[2-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]ethyl]carbamate(300 mg, 0.6 mmol, 1.00 equiv), and sodium hydride (72 mg, 1.8 mmol,3.00 equiv) in THF (10 mL) was stirred for 5 h at room temperature.After concentration, the residue was applied onto a silica gel columneluting with EtOAc/petroleum ether (1:1) to afford 100 mg crude of thetitle compound as a white solid.

Step 5: Synthesis of6-[4-[(4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrimidin-2-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of tert-butylN-[2-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-2-oxoethyl]-N-[2-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]ethyl]carbamate(80 mg, 0.11 mmol, 1.00 equiv) in hydrogen chloride/dioxane (10 mL) wasstirred for 2 h at room temperature. After concentration, the residuewas purified by C18 reverse phase chromatography eluting withwater/CH₃CN yielding the title compound (20.9 mg, 38%) as a white solid.LCMS (ESI, m/z): 505.23 [M+H]+, 1HNMR (300 MHz, Methanol-d4) δ 8.45 (d,J=2.4 Hz, 1H), 8.08 (s, 1H), 7.78 (dd, J=9.0, 2.3 Hz, 1H), 6.88 (d,J=6.0 Hz, 1H), 4.48-4.30 (m, 1H), 3.87-3.63 (m, 9H), 3.56 (s, 2H),3.48-3.41 (m, 1H), 2.78-2.63 (m, 2H), 2.39-2.28 (m, 1H), 2.10-1.98 (m,2H), 1.89-1.76 (m, 3H).

Example 90:(S)-(6-[4-(3-[[1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propyl)piperazin-1-yl]pyridine-3-carbonitrile;Formic Acid

Step 1: Synthesis of6-[4-(3-hydroxypropyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of 3-(piperazin-1-yl)propan-1-ol (1.44 g, 9.98 mmol, 1.00equiv), 6-chloropyridine-3-carbonitrile (1.38 g, 9.96 mmol, 1.00 equiv),and potassium carbonate (2 g, 14.47 mmol, 1.50 equiv) in DMF (20 mL) wasstirred for 1 h at 80° C. The solids were filtered out. The filtrate wasconcentrated under vacuum to afford 2.2 g (89%) of the title compound asa yellow solid. LCMS (ESI, m/z): 247.16 [M+H]⁺.

Step 2: Synthesis of Tert-Butyl(S)-2-([3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]propoxy]methyl)pyrrolidine-1-carboxylate

To a solution of(2S)-2-[(methanesulfonyloxy)methyl]pyrrolidine-1-carboxylate (3 g, 10.74mmol, 1.00 equiv), and6-[4-(3-hydroxypropyl)piperazin-1-yl]pyridine-3-carbonitrile (5.1 g,20.71 mmol, 1.50 equiv) in DMF (150 mL) was added sodium hydride (1 g,41.67 mmol, 2.00 equiv) in several batches, and the resulting solutionwas stirred for 6 h at 70° C. The mixture was extracted with 2×100 mL ofEtOAc and the organic layers were combined. The residue was applied ontoa silica gel column with EtOAc/petroleum ether to afford 1 g (22%) ofthe title compound as yellow oil. LCMS (ESI, m/z): 430.27 [M+H]⁺.

Step 3: Synthesis of(S)-6-[4-(3-[[pyrrolidin-2-yl]methoxy]propyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of tert-butyl(S)-2-([3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]propoxy]methyl)pyrrolidine-1-carboxylate(1 g, 2.33 mmol, 1.00 equiv) in dioxane/HCl (20 mL) was stirred for 1 hat 25° C. The residue was purified by C18 reverse phase chromatographyeluting with water/CH₃CN. The collected fractions were combined andconcentrated under vacuum to afford 600 mg (78%) of the title compoundas a yellow solid. LCMS (ESI, m/z): 330.22 [M+H]⁺.

Step 4: Synthesis of(S)-6-[4-(3-[[1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of Int-A6 (600 mg, 1.82 mmol, 1.00 equiv),(S)-6-[4-(3-[[pyrrolidin-2-yl]methoxy]propyl)piperazin-1-yl]pyridine-3-carbonitrile(600 mg, 1.82 mmol, 1.00 equiv), and TEA (5 mL) in ethanol (20 mL) wasstirred for 1 h at 50° C. The resulting mixture was concentrated undervacuum. The residue was purified by C18 reverse phase chromatographyeluting with water/CH₃CN to afford 600 mg (53%) of the title compound asyellow oil. LCMS (ESI, m/z): 622.31 [M+H]⁺.

Step 5: Synthesis of(S)-(6-[4-(3-[[1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propyl)piperazin-1-yl]pyridine-3-carbonitrileformic acid salt

A solution of6-[4-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propyl)piperazin-1-yl]pyridine-3-carbonitrile(600 mg, 0.96 mmol, 1.00 equiv), and TBAF (2.2 g, 8.41 mmol, 10.00equiv) in dioxane (20 mL) was stirred for 3 days at 70° C. Afterconcentrating, the residue was purified by Prep-HPLC yielding the titlecompound as a formate salt (21.8 mg, 4%) as a white solid. LCMS (ESI,m/z): 492.20 [M+H]⁺, ¹HNMR (DMSO-d₆, 400 MHz) δ: δ: 12.35 (s, 1H), 8.47(d, J=4.0 Hz, 1H), 8.14 (s, 1H), 8.05 (s, 1H), 7.85 (d, J=4.0 Hz, 1H),6.90 (d, J=12.0 Hz, 1H), 4.60-4.57 (s, 1H), 3.62-3.19 (m, 10H), 2.34 (t,4H), 2.24 (t, 2H), 2.10-2.07 (m, 1H), 1.87-1.91 (m, 1H), 1.55-1.67 (m,4H).

Example 91:6-(4-[2-[methyl([2-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]ethyl])amino]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1: Synthesis of6-[4-[2-([2-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]ethyl]amino)acetyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of5-[(2S)-2-(2-aminoethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(260 mg, 0.64 mmol, 1.00 equiv), Cs₂CO₃ (416 mg, 1.28 mmol, 2.00 equiv)and 6-[4-(2-bromoacetyl)piperazin-1-yl]pyridine-3-carbonitrile (196 mg,0.63 mmol, 1.00 equiv) in MeCN (13 mL) was stirred for 4 h at roomtemperature. The solids was filtered out, the resulting solution wasconcentrated under vacuum, and the residue was purified by C18 reversephase chromatography eluting with water/CH₃CN to afford 90 mg (22%) ofthe title compound as a yellow solid. LCMS (ESI, m/z): 635.31 [M+H]⁺.

Step 2: Synthesis of6-(4-[2-[methyl([2-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]ethyl])amino]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-[4-[2-([2-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]ethyl]amino)acetyl]piperazin-1-yl]pyridine-3-carbonitrile(90 mg, 0.14 mmol, 1.00 equiv), paraformaldehyde (19 mg, 0.21 mmol, 1.50equiv), potassium hydroxide (16 mg, 0.29 mmol, 2.00 equiv) and AcOH (0.1mL) in methanol (5 mL) was stirred for 1.5 h at room temperature. Thesolution was stirred for another 3 h at 60° C., NaBH₄ (10.7 mg, 0.28mmol, 2.00 equiv) was added, and the resulting solution was stirred foranother 30 min at room temperature. The resulting solution was quenchedwith 10 mL of water and extracted with 3×10 mL of EtOAc. The organiclayers were combined, washed with 1×10 mL of brine, dried over anhydroussodium sulfate and concentrated under vacuum to afford 90 mg (98%) ofthe title compound as a yellow oil. LCMS (ESI, m/z): 649.32[M+H]⁺.

Step 3: Synthesis of6-(4-[2-[methyl([2-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]ethyl])amino]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-(4-[2-[methyl([2-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]ethyl])amino]acetyl]piperazin-1-yl)pyridine-3-carbonitrile(80 mg, 0.12 mmol, 1 equiv) and TFA (1 mL) in DCM (5 mL) was stirred for1 h at room temperature. The resulting solution was concentrated undervacuum, and the residue was purified by Prep-HPLC yielding the titlecompound (11.4 mg, 17.83%) as a white solid. LCMS (ESI, m/z): 519.10[M+H]+, ¹HNMR (CD3OD-d₄, 300 MHz,) δ 8.44 (d, J=1.8 Hz, 1H), 8.04 (s,1H), 7.79 (dd, J=9.0, 2.4 Hz, 1H), 6.89 (d, J=9.3 Hz, 1H), 4.36 (s, 1H),3.77-3.61 (m, 10H), 3.43-3.35 (m, 2H), 2.65-2.43 (m, 2H), 2.41-2.29 (m,4H), 2.12-1.95 (m, 2H), 1.84-1.71 (m, 3H).

Example 92:6-[4-[(2E)-4-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)but-2-enoyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of5-[(2-hydroxyethyl)amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of Int-A6 (5 g, 15.21 mmol, 1 equiv), TEA (4.6 g, 45.46 mmol,2.989 equiv), and 2-aminoethan-1-ol (1.04 g, 17.03 mmol, 1.120 equiv) inEtOH (50 mL) was stirred for 5 h at 50° C. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (70/30) to afford 3.7 g(68.84%) of the title compound as yellow oil. LCMS (ESI, m/z): 354.14[M+H]⁺.

Step 2: Synthesis of methyl(2E)-4-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)but-2-enoate

A solution of5-[(2-hydroxyethyl)amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(2 g, 5.66 mmol, 1 equiv), methyl (2E)-4-bromobut-2-enoate (1.106 g,6.18 mmol, 1.092 equiv), Pd₂(dba)₃ (0.52 g, 0.57 mmol, 0.100 equiv),Ruphos (0.53 g, 1.14 mmol, 0.201 equiv), and Cs₂CO₃ (3.7 g, 11.36 mmol,2.007 equiv) in toluene (20 mL) was stirred for 4 h at 80° C. under anatmosphere of nitrogen. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (40/60) to afford 130 mg (5.09%) of the titlecompound as a yellow oil. LCMS (ESI, m/z): 452.18 [M+H]⁺.

Step 3: Synthesis of(2E)-4-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)but-2-enoicAcid

A solution of methyl(2E)-4-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)but-2-enoate(1.6 g, 3.54 mmol, 1 equiv), and LiOH-water (0.743 g, 17.71 mmol, 5.00equiv) in MeOH (30 mL) was stirred for 2 h at room temperature. Theresulting solution was extracted with 3×30 ml of EtOAc. The pH value ofthe solution was adjusted to 6 with HCl (35%). The solids were collectedby filtration to afford 300 mg (19.35%) of the title compound as yellowoil. LCMS (ESI, m/z): 438.16 [M+H]⁺.

Step 4: Synthesis of6-[4-[(2E)-4-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)but-2-enoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of(2E)-4-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)but-2-enoicacid (300 mg, 0.69 mmol, 1 equiv), Int-A4 (168.3 mg, 0.89 mmol, 1.30equiv), HATU (138.7 mg, 1.03 mmol, 1.50 equiv), and DIPEA (178 mg, 1.38mmol, 2.01 equiv) in DMF (4 mL) was stirred for 2 h at room temperature.After concentration, the residue was purified by C18 reverse phasechromatography eluting with water/CH₃CN to afford 140 mg (33.60%) of thetitle compound as a yellow oil. LCMS (ESI, m/z): 608.26 [M+H]⁺.

Step 5: Synthesis of6-(4-(2-(4-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)morpholin-3-yl)acetyl)piperazin-1-yl)nicotinonitrile

A solution of6-[4-[(2E)-4-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)but-2-enoyl]piperazin-1-yl]pyridine-3-carbonitrile(150 mg, 0.25 mmol, 1 equiv) in DCM (8 mL) was stirred for 1 h at roomtemperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with water/CH₃CN. The residue wasfurther purified by Prep-HPLC yielding the title compound (9.5 mg,8.06%) as a white solid. LCMS (ESI, m/z): 478.44 [M+H]⁺, ¹HNMR (300 MHz,DMSO-d₆) δ: 8.53 (d, J=2.2 Hz, 1H), 8.02 (s, 1H), 7.90 (dd, J=8.9, 2.5Hz, 1H), 6.96 (d, J=9.0 Hz, 1H), 4.36 (s, 1H), 3.84-3.62 (m, 13H),3.13-2.94 (m, 2H), 2.84 (d, J=6.0 Hz, 1H).

Example 93 Isomer A:6-[4-(3-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrileand Example 93 Isomer B:6-[4-(3-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl1-(hydroxymethyl)-2,3-dihydro-1H-isoindole-2-carboxylate

To a stirred solution of2-[(tert-butoxy)carbonyl]-2,3-dihydro-1H-isoindole-1-carboxylic acid(100 g, 379.81 mmol, 1.00 equiv) in THF (500 mL) at 0° C., BH₃.THF (1M,800 mL) was added dropwise. The resulting solution was stirred overnightat room temperature. The reaction was quenched with saturated aq. NaHCO₃at 0° C. The resulting mixture was concentrated under vacuum andextracted with 2 L EtOAc. The resulting mixture was washed with 5×500 mLof water and 2×500 mL of brine. The organic layer was dried overanhydrous sodium sulfate and concentrated under vacuum. This resulted in95 g (crude) of the title compound as oil. LCMS (ESI, m/z): 250.14[M+H]⁺.

Step 2: Synthesis of (2,3-dihydro-1H-isoindol-1-yl)methanolHydrochloride

A solution of tert-butyl1-(hydroxymethyl)-2,3-dihydro-1H-isoindole-2-carboxylate (95 g, 381.05mmol, 1.00 equiv) in hydrogen chloride/dioxane (800 mL) was stirred for2 h at room temperature. The solids were collected by filtration. Thisresulted in 63 g (89%) of the title compound as a white solid. LCMS(ESI, m/z): 150.09 [M+H]⁺

Step 3: Synthesis of5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]-methyl]-2,3-dihydropyridazin-3-one

A solution of (2,3-dihydro-1H-isoindol-1-yl)methanol hydrochloride (63g, 339.35 mmol, 1.00 equiv), Int-A6 (147 g, 80%) and TEA (104 mL) inethanol (500 mL) was stirred for 2 h at 60° C. The resulting mixture wasconcentrated under vacuum. The resulting solution was diluted with 2 Lof EtOAc. The resulting mixture was washed with 2×500 mL of NH₄Cl and2×500 mL of brine. The organic layer was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was dissolved in 500mL of EtOAc and added into 2.5 L hexane dropwise at 0° C. The solidswere collected by filtration. This resulted in 115 g (crude) of thetitle compound as a solid. LCMS (ESI, m/z): 442.18 [M+H]⁺.

Step 4: Synthesis of Tert-Butyl3-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)propanoate

To a stirred solution of5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(115 g, 260.46 mmol, 1.00 equiv) in MeCN (1.2 L), Cs₂CO₃ (127 g, 389.79mmol, 1.50 equiv) and tert-butyl prop-2-enoate (67 g, 522.74 mmol, 2.01equiv) were added. The resulting solution was stirred for 24 h at 35° C.and concentrated under vacuum. The residue was diluted with 2 L of EtOAcand washed with 2×500 mL of water and 500 mL of brine. The organic layerwas dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was applied onto a silica gel column with EtOAc/petroleumether (1:3). This resulted in 77 g (52%) of the title compound as awhite solid. LCMS (ESI, m/z): 570.26 [M+H]⁺.

Step 5: Synthesis of3-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)Propanoic Acid

A solution of tert-butyl3-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)propanoate(76 g, 133.40 mmol, 1.00 equiv) in hydrogen chloride/dioxane (1 L) wasstirred overnight at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was dissolved in 400 mL ofNH₃/MeOH and stirred at room temperature for 30 min. The resultingmixture was concentrated under vacuum. This resulted in 50 g (crude) ofthe title compound as a white solid. LCMS (ESI, m/z): 384.12 [M+H]⁺.

Step 6: Synthesis of6-[4-(3-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrileand6-[4-(3-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]propanoyl)-piperazin-1yl]-pyridine-3-carbonitrile

To a stirred solution of3-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)propanoicacid (50 g, 130.44 mmol, 1.00 equiv) in DMF (1 L), Int-A4 (45 g, 172.31mmol, 1.32 equiv), DIPEA (116 mL) and T3P (125 mL, 50% in EtOAc) wereadded. The resulting solution was stirred overnight at 30° C. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with water/CH₃CN. The residue was furtherpurified by Chiral-Prep-HPLC (CHIRALPAK IF-3, 0.46*5 cm; 3 um,(Hex:DCM=5:1)(0.1% DEA):EtOH=50:50, 1.0 ml/min) yielding the titlecompounds as off-white solids. The absolute stereochemistry was assignedbased on a protein X-ray crystal structure obtained of Example 18 IsomerB which confirmed (S)-absolute stereochemistry and was observed to bethe more potent enantiomer.

Example 93 Isomer A

20.5913 g, 85%, LCMS (ESI, m/z): 554.30 [M+H]⁺. ¹H NMR (400 MHz,Methanol-d₄) δ 8.44 (dd, J=2.4, 0.8 Hz, 1H), 8.27 (s, 1H), 7.78 (dd,J=9.1, 2.3 Hz, 1H), 7.43-7.37 (m, 1H), 7.33 (dd, J=4.8, 3.2 Hz, 3H),6.86 (d, J=9.2 Hz, 1H), 5.94-5.87 (m, 1H), 5.21 (d, J=14.7 Hz, 1H), 4.59(d, J=14.8 Hz, 1H), 3.93 (dd, J=10.2, 3.5 Hz, 1H), 3.82 (dt, J=9.3, 5.9Hz, 1H), 3.77-3.60 (m, 8H), 3.61-3.51 (m, 2H), 2.67-2.58 (m, 2H).Rt=2.690 min.

Example 93 Isomer B

20.7982 g, 86%, LCMS (ESI, m/z): 554.30 [M+H]⁺. Rt=3.263 min.

Example 94 Isomer A:6-[4-[(2R)-2-methyl-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl]piperazin-1-yl]pyridine-3-carbonitrileand Example 94 Isomer B:6-[4-[(2S)-2-methyl-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of methyl2-([[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]methyl)prop-2-enoate

To a solution of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(500 mg, 1.27 mmol, 1.00 equiv) and NBu₄I (93 mg, 0.25 mmol, 0.20 equiv)in toluene (16 mL) was added sodium hydride (91 mg, 3.79 mmol, 3.00equiv). After 30 min at room temperature, methyl2-(bromomethyl)prop-2-enoate (2.24 g, 12.51 mmol, 10.00 equiv) was addeddropwise. The resulting solution was stirred for 1.5 h at 80° C. Thereaction was quenched with 50 mL of water, extracted with 2×50 mL ofEtOAc, the organic layers were combined, washed with 50 mL of brine,dried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (28/72) to afford 549 mg (88%) of the titlecompound as yellow oil. LCMS(ESI, m/z): 492.21 [M+H]⁺.

Step 2: Synthesis of methyl2-methyl-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoate

Under an atmosphere of hydrogen, a solution of methyl2-([[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]methyl)prop-2-enoate(549 mg, 1.12 mmol, 1.00 equiv) and Pd/C (50 mg) in methanol (20 mL) wasstirred for 2 h at room temperature. The solids were filtered out, andthe resulting solution was concentrated under vacuum to afford 300 mg(54%) of the title compound as a yellow solid. LCMS (ESI, m/z):494.22[M+H]⁺.

Step 3: Synthesis of2-methyl-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicacid

A solution of methyl2-methyl-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoate(200 mg, 0.41 mmol, 1.00 equiv) and LiOH (58 mg, 2.42 mmol, 4.00 equiv)in THF (4 mL) and water (1 mL) was stirred for 2 h at room temperature.The resulting solution was diluted with 5 mL of water, extracted with3×10 mL of EtOAc, and the organic layers combined. The pH value of theresulting solution was adjusted to 4 with hydrogen chloride and thenconcentrated under vacuum. The residue was purified by C18 reverse phasechromatography eluting with water/CH₃CN to afford 236 mg of the titlecompound as a crude yellow solid. LCMS (ESI, m/z): 480.21 [M+H]⁺.

Step 4: Synthesis of2-methyl-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicAcid

A solution of2-methyl-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicacid (236 mg, 0.49 mmol, 1.00 equiv) and TFA (2 mL) in DCM (10 mL) wasstirred for 2 h at room temperature. The resulting mixture was dilutedwith 30 mL of EtOAc, extracted with 5 mL of water, and the aqueous layerwas concentrated under vacuum to afford 200 mg of the title compound asa solid. LCMS (ESI, m/z): 350.12[M+H]⁺.

Step 5:6-[4-[(2R)-2-methyl-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(2S)-2-methyl-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of2-methyl-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicacid (280 mg, 0.8 mmol, 1.00 equiv), HATU (305 mg, 0.8 mmol, 1.00equiv), DIPEA (310 mg, 2.4 mmol, 3.00 equiv) and Int-A4 (151 mg, 0.8mmol, 1.00 equiv) in DMF (10 mL) was stirred for 2 h at roomtemperature. The resulting solution was diluted with 10 mL of water,extracted with 3×10 mL of EtOAc and the organic layers were combined,washed with 10 mL of brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by C18 reverse phasechromatography eluting with water/CH₃CN. After concentration the residuewas further purified by Prep-HPLC and Chiral-HPLC yielding (afterarbitrary assignment of stereochemistry) the title compounds, as whitesolids.

Example 94 Isomer A

11.6 mg, 18.4%, LCMS (ESI, m/z): 520.30 [M+H]+, ¹HNMR (DMSO-d₆, 400MHz,) δ 12.35 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.00 (s, 1H), 7.90 (dd,J=9.2, 2.4 Hz, 1H), 6.93 (d, J=9.2 Hz, 1H), 4.52 (d, J=7.4 Hz, 1H),3.70-3.46 (m, 11H) 3.40-3.34 (m, 2H), 3.32 (d, J=5.5 Hz, 1H), 3.00 (dt,J=13.6, 6.8 Hz, 1H), 2.11-2.02 (m, 1H), 1.86 (d, J=6.4 Hz, 1H),1.68-1.52 (m, 2H), 0.93 (d, J=6.8 Hz, 3H).

Example 94 Isomer B

18 mg, 28.5%, LCMS (ESI, m/z): 520.25[M+H]+, ¹HNMR (DMSO-d₆, 400 MHz,) δ12.34 (s, 1H), 8.51 (d, J=2.4 Hz, 1H), 8.00 (s, 1H), 7.89 (dd, J=9.2,2.4 Hz, 1H), 6.92 (d, J=9.2 Hz, 1H), 4.53 (d, J=7.6 Hz, 1H), 3.69-3.48(m, 11H), 3.34-3.15 (m, 2H), 2.99 (d, J=6.8 Hz, 1H), 2.10-2.02 (m, 1H),1.87 (d, J=6.5 Hz, 1H), 1.71-1.54 (m, 2H), 0.91 (d, J=6.8 Hz, 3H).

Example 95:6-(4-((1R,3S)-3-(((S)-1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)cyclobutane-1-carbonyl)piperazin-1-yl)nicotinonitrileand 6-(4-((1S,3R)-3-(((S)-1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)cyclobutane-1-carbonyl)piperazin-1-yl)nicotinonitrile

Step 1: Tert-butyl(2S)-2-([[(4-methylbenzene)sulfonyl]oxy]methyl)pyrrolidine-1-carboxylate

A solution of tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate(2 g, 9.94 mmol, 1.00 equiv), TEA (2 g, 19.76 mmol, 2.00 equiv), DMAP(121 mg, 0.99 mmol, 0.10 equiv), TsCl (2.83 g, 14.8 mmol, 1.50 equiv) inDCM (20 mL) was stirred for overnight at 25° C. To the resultingsolution was added 20 mL of saturated sodium bicarbonate and theresulting solution was extracted with 3×20 mL of DCM and the organiclayers combined. The resulting solution was washed with 3×20 mL ofsaturated NH₄Cl, the organic layers combined and dried over anhydroussodium sulfate and concentrated under vacuum to afford 2.9 g (82%) ofthe title compound as a yellow oil. LCMS: [M+H]⁺ 356.15.

Step 2: Tert-butyl(2S)-2-[[3-(methoxycarbonyl)cyclobutoxy]methyl]pyrrolidine-1-carboxylate

A solution of methyl 3-hydroxycyclobutane-1-carboxylate (800 mg, 6.15mmol, 1.00 equiv), NaH (492 mg, 20.50 mmol, 2.00 equiv), tert-butyl(2S)-2-([[(4-methylbenzene)sulfonyl]oxy]methyl)pyrrolidine-1-carboxylate(2.2 g, 6.19 mmol, 1.00 equiv) in THF (20 mL) was stirred overnight at70° C. The residue was quenched with 20 mL of water, extracted with 3×20mL of EtOAc and the organic layers combined. The resulting solution waswashed with 3×20 mL of saturated NH₄Cl, the organic layers combined anddried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN to afford 250 mg (13%) of the title compound as a yellow oil.LCMS: [M+H]⁺ 314.19.

Step 3: Methyl 3-[(2S)-pyrrolidin-2-ylmethoxy]cyclobutane-1-carboxylateHydrochloride

A solution of tert-butyl (2S)-2-[[3-(methoxycarbonyl)cyclobutoxy]methyl]pyrrolidine-1-carboxylate(250 mg, 0.80 mmol, 1.00 equiv) in dioxane/HCl (15 mL, 4M) was stirredfor 1 h at 25° C. The resulting solution was concentrated under vacuumto afford 250 mg of the title compound as a yellow crude oil. LCMS:[M+H]⁺ 250.11.

Step 4: Methyl3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclobutane-1-carboxylate

A solution of Int-A6 (262 mg, 0.80 mmol, 1.00 equiv), TEA (242 mg, 2.39mmol, 3.00 equiv), methyl3-[(2S)-pyrrolidin-2-ylmethoxy]cyclobutane-1-carboxylate hydrochloride(250 mg, 1.00 mmol, 1.00 equiv) in EtOH (15 mL) was stirred for 2 h at60° C. The resulting solution was concentrated and the residue wasapplied onto a silica gel column with EtOAc/petroleum ether (1/4) toafford 320 mg (79%) of the title compound as a yellow oil. LCMS: [M+H]⁺506.22.

Step 5: Methyl3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclobutane-1-carboxylate

A solution of methyl3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclobutane-1-carboxylate(320 mg, 0.63 mmol, 1.00 equiv), TFA (2 mL) in DCM (20 mL) was stirredfor 2 h at 25° C. The pH value of the solution was adjusted to 8 withethanolamine. The resulting solution was extracted with 3×20 mL of DCMand the organic layers combined, dried over anhydrous sodium sulfate andconcentrated under vacuum to afford 260 mg of the title compound asyellow oil. LCMS: [M+H]⁺ 376.16.

Step 6:3-[[(2S)-1-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclobutane-1-carboxylicAcid

A solution of methyl3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclobutane-1-carboxylate(260 mg, 0.69 mmol, 1.00 equiv), LiOH.H₂O (200 mg, 4.77 mmol, 5.00equiv) in MeOH (20 mL) and water (4 mL) was stirred for 2 h at 25° C.The pH value of the solution was adjusted to 4 with HCl (2M). Theresulting solution was filtered and the solid was collected to afford115 mg (46%) of the title compound as a yellow solid. LCMS: [M+H]⁺362.12.

Step 7:6-(4-((1R,3S)-3-(((S)-1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)cyclobutane-1-carbonyl)piperazin-yl)piperazin-1-yl)nicotinonitrileand6-(4-((1S,3R)-3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)cyclobutane-1-carbonyl)piperazin-1-yl)nicotinonitrile

A solution of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]cyclobutane-1-carboxylicacid (100 mg, 0.28 mmol, 1.00 equiv), DIPEA (107 mg, 0.83 mmol, 3.00equiv), Int-A4 (68 mg, 0.36 mmol, 1.10 equiv), HATU (116 mg, 0.31 mmol,1.10 equiv) in DMF (8 mL) was stirred for 1 h at 25° C. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN. The residue was further purifiedby Prep-HPLC and Chiral-Prep-HPLC (CHIRALPAK IG-3, 3 μm, 0.46×10 cmcolumn, eluting with a gradient of MtBE (0.1% DEA):EtOH (50:50), at aflow rate of 1 mL/min) yielding (after arbitrary assignment of thestereochemistry) the title compounds, respectively, as white solids,isomer A LCMS: [M+H]⁺ 532.22; ¹H NMR (400 MHz, Methanol-d₄) δ: 8.43 (dd,J=2.3, 0.7 Hz, 1H), 8.19 (s, 1H), 7.77 (dd, J=9.1, 2.4 Hz, 1H), 6.88(dd, J=9.1, 0.8 Hz, 1H), 4.89-4.33 (m, 1H), 4.04 (p, J=6.0 Hz, 1H),3.79-3.63 (m, 7H), 3.57 (dd, J=10.0, 3.5 Hz, 1H), 3.49 (dd, J=6.6, 4.1Hz, 2H), 3.44-3.37 (m, 1H), 3.35 (s, 1H), 3.33-3.18 (m, 1H), 2.62-2.39(m, 2H), 2.24 (d, J=6.9 Hz, 1H), 2.19-1.89 (m, 3H), 1.74 (tt, J=17.3,6.0 Hz, 2H). tR=3.607 min and isomer B LCMS: [M+H]⁺ 532.22; ¹H NMR (400MHz, Methanol-d₄) δ: 8.43 (dd, J=2.3, 0.8 Hz, 1H), 8.13 (s, 1H), 7.77(dd, J=9.1, 2.3 Hz, 1H), 6.87 (dd, J=9.1, 0.9 Hz, 1H), 4.84-4.31 (m,1H), 4.05-3.88 (m, 1H), 3.88-3.61 (m, 7H), 3.56 (dt, J=10.7, 4.0 Hz,3H), 3.46-3.34 (m, 2H), 3.06-2.85 (m, 1H), 2.70-2.43 (m, 2H), 2.25 (d,J=6.9 Hz, 1H), 2.18-1.80 (m, 3H), 1.74 (td, J=11.3, 7.1 Hz, 2H).tR=5.473 min.

Example 96:6-[4-[(3Z)-4-[[(2S)-1-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-3-enoyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(2E)-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-2-enoyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Methyl(2E)-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-2-enoate

A solution of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(600 mg, 1.52 mmol, 1.00 equiv), Cs₂CO₃ (995 mg, 3.05 mmol, 2.00 equiv),[Pd(ally)Cl]₂ (28 mg, 0.05 equiv), Rockphos (71 mg, 0.10 equiv), methyl(2E)-4-bromobut-2-enoate (1.36 g, 7.60 mmol, 5.00 equiv) in toluene (16mL) was stirred for 2 h at 80° C. After concentration under reducedpressure, the residue was purified by silica gel column chromatographyeluting with EtOAc/petroleum ether to afford 370 mg (49%) of the titlecompound as a yellow solid. LCMS: [M+H]⁺ 492.21.

Step 2:(2E)-4-[[(2S)-1-[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-2-enoicAcid

A solution of methyl(2E)-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-2-enoate(350 mg, 0.71 mmol, 1.00 equiv), LiOH (30 mg, 1.25 mmol, 1.00 equiv) inMeOH (1.5 mL) and water (1.5 mL) was stirred for 12 h at RT. Theresulting mixture was concentrated under reduced pressure to afford 200mg of the title compound. LCMS: [M+H]⁺ 478.19.

Step 3:(2E)-4-[[(2S)-1-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-2-enoicAcid

A solution of(2E)-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-2-enoicacid (200 mg, 0.42 mmol, 1.00 equiv) in TFA (2 mL) and DCM (10 mL) wasstirred for 2 h at RT. After concentration, the residue was purified byC18 reverse phase chromatography eluting with H₂O/CH₃CN to afford 90 mg(62%) of the title compound as a white solid. LCMS: [M+H]⁺ 348.11.

Step 4:6-[4-[(3Z)-4-[[(2S)-1-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-3-enoyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(3E)-4-[[(2S)-1-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-2-enoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of(2E)-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-2-enoicacid (80 mg, 0.23 mmol, 1 equiv), DIPEA (119.1 mg, 0.92 mmol, 4 equiv),HATU (87.6 mg, 0.23 mmol, 1.00 equiv), Int-A4 (43.4 mg, 0.23 mmol, 1.00equiv) in DMF (2 mL) was stirred for 2 h at RT. The crude product waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CNyielding the title compounds, respectively, as white solids, isomer A(4.2 mg, 3.5%). LCMS: [M+H]⁺ 518.20; ¹H NMR (CD₃OD, 300 MHz) δ: 8.45(dd, J=2.4, 0.8 Hz, 1H), 8.22 (s, 1H), 7.79 (dd, J=9.1, 2.4 Hz, 1H),6.89 (dd, J=9.2, 0.8 Hz, 1H), 6.18 (d, J=6.1, 1.6 Hz, 1H), 4.81-4.72 (m,1H), 4.57 (q, J=6.9 Hz, 1H), 4.04 (dd, J=10.8, 3.4 Hz, 1H), 3.84-3.62(m, 8H), 3.57 (d, J=5.3 Hz, 2H), 3.41 (d, J=11.1 Hz, 1H), 3.10 (dd,J=7.2, 0.6 Hz, 2H), 2.33-2.22 (m, 1H), 2.10-1.98 (m, 1H), 1.87-1.60 (m,2H), 1.40-1.28 (m, 1H) and isomer B (604 mg, 5.4%), LCMS: [M+H]⁺ 518.20;¹H NMR (CD₃OD, 300 MHz) δ: 8.46 (dd, J=2.4, 0.8 Hz, 1H), 8.31 (s, 1H),7.80 (dd, J=9.1, 2.4 Hz, 1H), 6.93 (dd, J=9.1, 0.8 Hz, 1H), 6.83 (dt,J=15.2, 3.6 Hz, 1H), 6.47 (dt, J=15.2, 2.1 Hz, 1H), 4.82-4.68 (m, 1H),4.33-4.10 (m, 2H), 3.90-3.60 (m, 10H), 3.50-3.38 (m, 2H), 2.45-2.20 (m,1H), 2.10-1.95 (m, 1H), 1.86-1.59 (m, 2H), 1.40-1.30 (m, 1H).

Example 97:6-[4-[4-([1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-3-yl]methoxy)cyclohexanecarbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Methyl4-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-3-yl]methoxy)benzoate

Under nitrogen, a solution of5-[3-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(300 mg, 0.76 mmol, 1.00 equiv), methyl 4-bromobenzoate (242 mg, 1.13mmol, 1.50 equiv), Pd[(allyl)Cl_(2]2) (30 mg, 0.10 equiv), Rockphos (60mg, 0.20 equiv) and Cs₂CO₃ (480 mg, 2.00 equiv) in toluene (3 mL) wasstirred for 1 h at 80° C., and then the resulting solution was dilutedwith 50 mL of EtOAc and washed with 3×40 mL of H₂O, and then the organiclayers were concentrated under reduced pressure and the residue waspurified by silica gel column chromatography eluting withEtOAc/petroleum ether (46/54, v/v) to afford 330 mg (82%) of the titlecompound as a yellow oil. LCMS: [M+H]⁺ 528.21.

Step 2: Methyl4-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-3-yl]methoxy)cyclohexane-1-carboxylate

Under a hydrogen atmosphere, a solution of methyl4-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-3-yl]methoxy)benzoate(295 mg, 0.56 mmol, 1.00 equiv) and Rh/Al₂O₃ (600 mg, 2.00 equiv) inMeOH (10 mL) was stirred for 16 h at RT, and then the solids werefiltered out, and the resulting solution was concentrated under vacuumto afford 310 mg of crude title compound as a yellow green oil. LCMS:[M+H]⁺ 534.25.

Step 3:4-([1-[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-3-yl]methoxy)cyclohexane-1-carboxylicacid

A solution of methyl4-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-3-yl]methoxy)cyclohexane-1-carboxylate(290 mg, 0.54 mmol, 1.00 equiv) and LiOH (136 mg) in water (0.5 mL) andTHF (2.5 mL) was stirred for 16 h at 40° C., and then the resultingsolution was concentrated under vacuum and the residue was purified byC18 reverse phase chromatography eluting with H₂O/CH₃CN to afford 145 mg(51%) of the title compound as a yellow oil. LCMS: [M+H]⁺ 520.24.

Step 4:4-([1-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-3-yl]methoxy)cyclohexane-1-carboxylicAcid

A solution of4-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-3-yl]methoxy)cyclohexane-1-carboxylicacid (145 mg, 0.28 mmol, 1.00 equiv) and TFA (0.5 mL) in DCM (2.5 mL)was stirred for 2 h at RT, and then the resulting solution wasconcentrated under vacuum to afford 120 mg of the title compound as ayellow oil. LCMS: [M+H]⁺ 390.16.

Step 5:6-[4-[4-([1-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-3-yl]methoxy)cyclohexanecarbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of4-([1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-3-yl]methoxy)cyclohexane-1-carboxylicacid (120 mg, 0.31 mmol, 1.00 equiv), Int-A4 (62 mg, 0.33 mmol, 1.10equiv), HATU (114 mg, 0.30 mmol, 1.00 equiv) and DIPEA (77 mg, 0.60mmol, 2.00 equiv) in DMF (5 mL) was stirred for 1 h at RT and then theresulting solution was purified by C18 reverse phase chromatographyeluting with H₂O/CH₃CN. After concentration by reduced pressure, theresidue was further purified by Prep-HPLC yielding the title compound asa white solid (13.8 mg, 8%). LCMS: [M+H]⁺ 560.30. ¹H NMR (Methanol-d₄,300 MHz) δ 8.44 (d, J=1.8 Hz, 1H), 7.94 (s, 1H), 7.79 (dd, J=9.0, 2.4Hz, 1H), 6.90 (d, J=8.7 Hz, 1H), 3.86-3.69 (m, 11H), 3.59-3.43 (m, 4H),2.79-2.71 (m, 1H), 2.63-2.54 (m, 1H), 2.20-2.10 (m, 1H), 2.03-1.78 (m,5H), 1.55 (t, J=12.9 Hz, 4H).

Example 98:6-[4-(3-[[(2S)-1-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Methyl3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoate

A solution of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(Example 31, Step 1; 1.97 g, 5.01 mmol, 1.00 equiv), NaH (2 g, 83.3mmol, 10.0 equiv), methyl prop-2-enoate (1.72 g, 20.0 mmol, 4.00 equiv)in THF (100 mL) was stirred overnight at RT. The reaction was thenquenched by the addition of 200 mL of water. The resulting solution wasextracted with 3×150 mL of EtOAc and the organic layers combined andconcentrated under vacuum. The residue was purified by silica gelchromatography using EtOAc/petroleum ether (3/1, v/v) to afford 700 mg(29%) of the title compound as a light yellow solid. LCMS: [M+H]⁺480.21.

Step 2: Methyl3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoate

A solution of methyl3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoate(700 mg, 1.46 mmol, 1.00 equiv) in HCl/dioxane (30 mL) was stirredovernight at RT. The resulting mixture was concentrated under vacuum toafford 500 mg of the title compound. LCMS: [M+H]⁺ 350.12.

Step 3:3-[[(2S)-1-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoic

A solution of methyl3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoate(500 mg, 1.43 mmol, 1.00 equiv), LiOH (171 mg, 7.41 mmol, 5.00 equiv) inMeOH (20 mL) and water (5 mL) was stirred for 2 h at RT. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford 120 mg of the titlecompound. LCMS: [M+H]⁺ 336.11.

Step 4:6-[4-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicacid (110 mg, 0.33 mmol, 1.00 equiv), HATU (125 mg, 0.33 mmol, 1.00equiv), DIPEA (170 mg, 1.32 mmol, 4.00 equiv), Int-A (62 mg, 0.33 mmol,1.00 equiv) in DMF (2 mL) was stirred for 30 min at RT. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford the title compound (77.7mg 47%) as a white solid. LCMS: [M+H]⁺ 506.20, ¹H NMR (Methanol-d₄, 300MHz) δ: 8.42-8.41 (d, J=2.3 Hz, 1H), 8.12 (s, 1H), 7.77-7.73 (dd, J=9.1,2.3 Hz, 1H), 6.86-6.84 (d, J=9.0 Hz, 1H), 4.59-4.55 (dd, J=7.8, 3.8 Hz,1H), 3.82-3.61 (m, 12H), 3.45-3.30 (m, 2H), 2.64-2.59 (td, J=5.9, 2.0Hz, 2H), 2.22-2.18 (dr, 1H), 1.98-1.93 (p, J=5.4, 4.7 Hz, 1H), 1.69-1.63(br s, 2H).

Example 99:N-[4-[(5-cyanopyridin-2-yl)oxy]cyclohexyl]-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanamide

Step 1: Synthesis of Tert-ButylN-[4-[(5-cyanopyridin-2-yl)oxy]cyclohexyl]carbamate

A solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (2.26 g, 10.50mmol, 1.05 equiv), sodium hydride (440 mg, 18.3 mmol, 1.10 equiv),6-chloropyridine-3-carbonitrile (1.38 g, 9.96 mmol, 1.00 equiv) in DMF(45 mL) was stirred for 2 h at room temperature. The resulting solutionwas quenched with 30 ml water, extracted with EtOAc (3×30 mL) and theorganic layers combined. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column withEtOAc/petroleum ether (1:4) to afford 2 g (63%) of the title compound asa white solid. LCMS (ESI, m/z): 318.18 [M+H]⁺

Step 2: Synthesis of 6-(4-aminocyclohexyloxy)nicotinonitrile hydrogenchloride

A solution of tert-butylN-[4-[(5-cyanopyridin-2-yl)oxy]cyclohexyl]carbamate (146 mg, 0.46 mmol,1.00 equiv) in hydrogen chloride/dioxane (3 mL) was stirred for 6 min atroom temperature. The resulting mixture was concentrated under vacuum toafford 1.2 g crude of the title compound as a white solid. LCMS (ESI,m/z): 218.13 [M+H]⁺

Step 3: Synthesis ofN-[4-[(5-cyanopyridin-2-yl)oxy]cyclohexyl]-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanamide

A solution of 6-(4-aminocyclohexyloxy)nicotinonitrile hydrogen chloride(52 mg, 0.24 mmol, 1.20 equiv),3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicacid (70 mg, 0.21 mmol, 1.00 equiv), HATU (100 mg, 0.26 mmol, 1.50equiv), DIPEA (62 mg, 0.48 mmol, 2.00 equiv) in DMF (40 mL) was stirred2 h at room temperature. After concentration, the residue was purifiedby C18 reverse phase chromatography eluting with H₂O/CH₃CN. Then theresidue was further purified by Prep-HPLC yielding the title compound(46.3 mg 41%) as a white solid. LCMS (ESI, m/z): 535.30 [M+H]⁺, ¹H NMR(300 MHz, Chloroform-d) δ 8.53 (s, 1H), 8.15 (s, 1H), 7.95 (dd, J=8.7,2.4 Hz, 1H), 6.87 (dd, J=8.7, 0.8 Hz, 1H), 5.09-4.91 (m, 1H), 4.69-4.68(m, 1H), 3.75-3.60 (m, 5H), 3.49-3.34 (m, 2H), 2.40-2.36 (m, 2H),2.21-2.15 (m, 3H), 2.06-1.97 (m, 3H), 1.74-1.57 (m, 4H), 1.44-1.39 (m,2H).

Example 100:6-[(3R)-3-methyl-4-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrileand6-[(3S)-3-methyl-4-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate

A solution of tert-butyl piperazine-1-carboxylate (1 g, 5.37 mmol, 1.00equiv), 6-chloropyridine-3-carbonitrile (690 mg, 4.98 mmol, 1.00 equiv),potassium carbonate (1.4 g, 10.13 mmol, 2.00 equiv), NMP (20 mL) wasstirred for 1 h at 80° C. The resulting solution was quenched by 100 mlof water and extracted with 2×100 mL of EtOAc and the organic layerscombined and concentrated under vacuum to afforded 1.2 g (78%) of thetitle compound as yellow oil. LCMS (ESI, m/z): 303.15 [M+H]⁺

Step 2. Synthesis of 6-(piperazin-1-yl)pyridine-3-carbonitrileHydrochloride

A solution of tert-butyl 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate(1.2 g, 4.16 mmol, 1.00 equiv), dioxane/HCl (10 mL). The resultingsolution was stirred for 30 min at 25° C. The solids were collected byfiltration to afforded 800 mg (86%) of the title compound as a whitesolid. LCMS (ESI, m/z): 203.22 [M+H]⁺

Step 3. Synthesis of6-[(3R)-3-methyl-4-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrileand6-[(3S)-3-methyl-4-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxypropanoicacid (100 mg, 0.30 mmol, 1.00 equiv),6-(3-methylpiperazin-1-yl)pyridine-3-carbonitrile hydrochloride (60 mg,0.25 mmol, 1.00 equiv), HATU (110 mg, 0.29 mmol, 1.00 equiv), DIPEA (1mL), DMF (2 mL). The resulting solution was stirred for 2 h at 25° C.After concentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN. Then the residue was furtherpurified by Prep-HPLC and Chiral-Prep-HPLC yielding (after arbitraryassignment of the stereochemistry) the title compounds, respectively, aswhite solids, isomer A (6.0 mg, 15%). LCMS (ESI, m/z): 520.30 [M+H]⁺,¹HNMR (DMSO-d₆, 400 MHz) δ: 12.07 (s, 1H), 8.42 (d, J=2.4 Hz, 1H), 7.93(s, 1H), 7.81 (d, J=4.0 Hz, 1H), 6.86 (d, J=11.6 Hz, 1H), 4.60-4.30 (m,2H), 4.25-4.18 (m, 2H), 4.01-3.80 (br, 1H), 3.72-3.58 (m, 2H), 3.50-3.10(m, 7H), 2.62-3.32 (m, 2H), 2.15-2.01 (br, 1H), 1.98-1.82 (br, 1H),1.68-1.73 (m, 2H), 1.12-1.23 (d, J=8.8 Hz, 3H). tR=1.238 min (CHIRALPAKIG, 20*250 mm, 5 um, Hex (0.1% DEA):EtOH=80:20, 1.0 mL/min) and isomer B(4.7 mg, 12%) as a white solid. LCMS (ESI, m/z): 520.30 [M+H]⁺, tR=1.233min (CHIRAL Cellulose-SB, 0.46*15 cm; 5 um, Hex(0.1% DEA):EtOH=80:20,1.0 mL/min). ¹HTME-NMR (DMSO-d₆, 353 k, 400 MHz) δ: 12.07 (s, 1H), 8.42(d, J=2.4 Hz, 1H), 7.93 (s, 1H), 7.81 (d, J=4.0 Hz, 1H), 6.86 (d, J=11.6Hz, 1H), 4.60-4.30 (m, 2H), 4.25-4.18 (m, 2H), 4.01-3.80 (br, 1H),3.72-3.58 (m, 2H), 3.50-3.10 (m, 7H), 2.62-3.32 (m, 2H), 2.15-2.01 (br,1H), 1.98-1.82 (br, 1H), 1.68-1.73 (m, 2H), 1.12-1.23 (d, J=8.8 Hz, 3H).

Example 101:6-[5-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)-2,5-diazabicyclo[2.2.2]octan-2-yl]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl5-(5-cyanopyridin-2-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate

A solution of tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (1g, 4.71 mmol, 1.00 equiv), potassium carbonate (1.3 g, 9.41 mmol, 2.00equiv), 6-chloropyridine-3-carbonitrile (651 mg, 4.70 mmol, 1.00 equiv)in DMF (10 mL) was stirred for 2 h at 80° C. in an oil bath. Afterconcentration, the residue was applied onto a silica gel column elutingwith EtOAc/petroleum ether (1:3) to afford 940 mg (63%) of the titlecompound as a solid. LCMS (ESI, m/z): 315.17 [M+H]⁺

Step 2: Synthesis of6-[2,5-diazabicyclo[2.2.2]octan-2-yl]pyridine-3-carbonitrileHydrochloride

A solution of tert-butyl5-(5-cyanopyridin-2-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (300mg, 0.95 mmol, 1.00 equiv) in hydrogen chloride/dioxane (5 mL) wasstirred for 1 h at room temperature. After filtration, the filtrate wasconcentrated under reduced pressure to afford 180 mg (75%) of the titlecompound as a solid. LCMS (ESI, m/z): 215.12 [M−Cl]⁺

Step 3: Synthesis of6-[5-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)-2,5-diazabicyclo[2.2.2]octan-2-yl]pyridine-3-carbonitrile

A solution of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicacid (100 mg, 0.30 mmol, 1.00 equiv), HATU (114 mg, 0.30 mmol, 1.00equiv), DIPEA (155 mg, 1.20 mmol, 4.00 equiv),6-2,5-diazabicyclo[2.2.2]octan-2-ylpyridine-3-carbonitrile hydrochloride(86 mg, 0.30 mmol, 1.00 equiv) in DMF (2 mL) was stirred for 1 h at roomtemperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN and purified byPrep-HPLC yielding the title compound (42.7 mg 27%) as a white solid.LCMS (ESI, m/z): 532.22 [M+H]⁺, ¹H NMR (Methanol-d₄, 400 MHz) δ:8.39-8.38 (d, J=2.3 Hz, 1H), 8.11-8.07 (m, 1H), 7.75-7.71 (dt, J=9.0,2.1 Hz, 1H), 6.55-6.65 (dr, 1H), 5.05 (dr, 1H), 4.56-4.49 (dr, 2H),3.79-3.36 (m, 10H), 2.64-2.56 (m, 1H), 2.51-2.47 (m, 1H), 2.17 (dr, 1H),2.03-1.88 (m, 5H), 1.69-1.67 (d, J=5.9 Hz, 2H).

Example 102:6-[3-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl8-(5-cyanopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

A solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1g, 4.71 mmol, 1.00 equiv), potassium carbonate (1.3 g, 9.41 mmol, 2.00equiv), 5-chloropyridin-2-carbonitrile (651 mg, 4.67 mmol, 1.00 equiv)in DMF (10 mL) was stirred for 2 h at 80° C. in an oil bath. The solidswere filtered out. The resulting solution was extracted with 3×20 mL ofether and the organic layers combined. After concentration, the residuewas applied onto a silica gel column eluting with EtOAc/petroleum ether(1:2) to afford 1 g (68%) of the title compound as a solid. LCMS (ESI,m/z): 315.17 [M+H]⁺

Step 2: Synthesis of6-3,8-diazabicyclo[3.2.1]octan-8-ylpyridine-3-carbonitrile Hydrochloride

A solution of tert-butyl8-(5-cyanopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (300mg, 0.95 mmol, 1.00 equiv) in dioxane/HCl (10 mL) was stirred for 1 h atroom temperature. The solids were collected by filtration to afford 170mg (83%) of the title compound as a yellow solid. LCMS (ESI, m/z):215.12 [M−Cl]⁺

Step 3: Synthesis of6-[3-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]pyridine-3-carbonitrile

A solution of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicacid (100 mg, 0.30 mmol, 1.00 equiv), HATU (114 mg, 0.30 mmol, 1.00equiv), DIPEA (155 mg, 1.20 mmol, 4.00 equiv),6-3,8-diazabicyclo[3.2.1]octan-8-ylpyridine-3-carbonitrile hydrochloride(86 mg, 0.30 mmol, 1.00 equiv) in DMF (2 mL) was stirred for 1 h at roomtemperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN and purified byPrep-HPLC yielding the title compound (85.4 mg 54%) as a white solid.LCMS (ESI, m/z): 532.22 [M+H]⁺, ¹H NMR (Methanol-d₄, 400 MHz) δ: 8.42(dd, J=2.4, 0.8 Hz, 1H), 8.09 (d, J=4.2 Hz, 1H), 7.75 (dd, J=9.0, 2.3Hz, 1H), 6.84 (dd, J=9.0, 0.8 Hz, 1H), 4.85 (m, 1H) 4.71 (dr, 2H), 4.55(dr, 1H), 4.27-4.23 (d, J=13.1 Hz, 1H), 3.75-3.69 (m, 5H), 3.44-3.41 (m,2H), 2.91-2.86 (d, J=13.3 Hz, 1H), 2.60-2.55 (m, 2H), 2.03-2.01 (dr,1H), 1.96-1.82 (m, 3H), 1.75-1.68 (m, 4H).

Example 103:6-[2-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)-2,8-diazaspiro[4.5]decan-8-yl]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl8-(5-cyanopyridin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate

A solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (300mg, 1.25 mmol, 1.00 equiv), 6-chloropyridine-3-carbonitrile (345 mg,2.49 mmol, 2.00 equiv) and potassium carbonate (345 mg, 2.50 mmol, 2.00equiv) in NMP (10 mL) was stirred for 1 h at 80° C., and then theresulting solution was diluted with 45 mL of water, extracted with 2×20mL of EtOAc, and then the organic layers combined and concentrated undervacuum to afford 650 mg (crude) of the title compound as a brown solid.LCMS (ESI, m/z): 343.21 [M+H]⁺

Step 2: Synthesis of6-[2,8-diazaspiro[4.5]decan-8-yl]pyridine-3-carbonitrile

A solution of tert-butyl8-(5-cyanopyridin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (640 mg,1.87 mmol, 1.00 equiv) and TFA (1 mL) in DCM (5 mL) was stirred for 1 hat room temperature, and then the resulting solution was concentratedunder vacuum to afford 1 g (crude) of the title compound as brown oil.LCMS (ESI, m/z): 243.16 [M+H]⁺.

Step 3: Synthesis of6-[2-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)-2,8-diazaspiro[4.5]decan-8-yl]pyridine-3-carbonitrile

A solution of 6-[2,8-diazaspiro[4.5]decan-8-yl]pyridine-3-carbonitrile(109 mg, 0.45 mmol, 1.50 equiv),3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicacid (100 mg, 0.30 mmol, 1.00 equiv), HATU (114 mg, 0.30 mmol, 1.00equiv) and DIPEA (77 mg, 0.60 mmol, 2.00 equiv) in DMF (2 mL) wasstirred for 1 h at room temperature, and then the resulting solution waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN.After concentration, and then the residue was further purified byPrep-HPLC yielding the title compound (97 mg, 58%) as a white solid.LCMS (ESI, m/z): 560.30 [M+H]⁺, ¹HNMR (Methanol-d₄, 300 MHz) δ 8.44 (d,J=1.8 Hz, 1H), 7.94 (s, 1H), 7.79 (dd, J=9.0, 2.4 Hz, 1H), 6.90 (d,J=8.7 Hz, 1H), 3.86-3.69 (m, 11H), 3.59-3.43 (m, 4H), 2.79-2.71 (m, 1H),2.63-2.54 (m, 1H), 2.20-2.10 (m, 1H), 2.03-1.78 (m, 5H), 1.55 (t, J=12.9Hz, 4H).

Example 104:6-[8-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)-2,8-diazaspiro[4.5]decan-2-yl]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl2-(5-cyanopyridin-2-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate

A solution of tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (300mg, 1.25 mmol, 1.00 equiv), K₂CO₃ (345 mg, 2.50 mmol, 2.00 equiv) and6-bromopyridine-3-carbonitrile (465 mg, 2.54 mmol, 2.00 equiv) in NMP(20 mL) was stirred for 2 h at 80° C. in an oil bath, and then theresulting solution was diluted with 200 mL of H2O, extracted with 3×50mL of EtOAc and the organic layers combined, washed with 1×50 mL ofbrine, dried over anhydrous sodium sulfate and concentrated under vacuumto afford 220 mg (51%) of the title compound as a brown solid. LCMS(ESI, m/z): 343.21[M+H]⁺.

Step 2: Synthesis of6-[2,8-diazaspiro[4.5]decan-2-yl]pyridine-3-carbonitrile

A solution of tert-butyl2-(5-cyanopyridin-2-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg,0.58 mmol, 1.00 equiv) and TFA (1.5 mL) in DCM (7 mL) was stirred for 1h at room temperature, and then the resulting solution was concentratedunder vacuum to afford 155 mg (57.5%) of the title compound as a brownsolid. LCMS (ESI, m/z): 243.16 [M+H]⁺.

Step 3: Synthesis of6-[8-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)-2,8-diazaspiro[4.5]decan-2-yl]pyridine-3-carbonitrile

A solution of3-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxypropanoicacid (100 mg, 0.30 mmol, 1.20 equiv), HATU (100 mg, 0.26 mmol, 1.00equiv), DIPEA (67 mg, 0.52 mmol, 2.00 equiv) and6-[2,8-diazaspiro[4.5]decan-2-yl]pyridine-3-carbonitrile (51 mg, 0.21mmol, 1.00 equiv) in DMF (15 mL) was stirred for 40 min at roomtemperature, and then the resulting solution was diluted with 50 mL ofH2O, extracted with 3×50 mL of EtOAc and the organic layers combined,washed with 1×50 mL of brine and concentrated under vacuum, and then theresidue was purified by Prep-HPLC yielding the title compound (45.6 mg,45.6%) as a white solid. LCMS (ESI, m/z): 560.15 [M+H]+, ¹HNMR (CD3OD,300 MHz) δ 8.38 (d, J=2.3 Hz, 1H), 8.15 (s, 1H), 7.74 (dd, J=9.0, 2.4Hz, 1H), 6.61 (d, J=9.0 Hz, 1H), 4.61 (s, 1H), 3.82-3.36 (m, 14H), 2.61(d, J=4.8 Hz, 2H), 2.25-2.21 (m, 1H), 2.05-1.97 (m, 3H), 1.76-1.57 (m,6H).

Example 105:6-[2-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)-2,7-diazaspiro[3.5]nonan-7-yl]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl7-(5-cyanopyridin-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

A solution of tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (300mg, 1.33 mmol, 1.00 equiv), 6-chloropyridine-3-carbonitrile (495 mg,3.57 mmol, 2.00 equiv) and K₂CO₃ (375 mg, 2.71 mmol, 2.00 equiv) in NMP(20 mL) was stirred for 2 h at 80° C., and then the resulting solutionwas diluted with 200 mL of H2O, extracted with 3×50 mL of EtOAc and theorganic layers combined, washed with 1×50 mL of brine, dried overanhydrous sodium sulfate and concentrated under vacuum to afford 336 mg(77%) of the title compound as a brown solid. LCMS (ESI, m/z):329.19[M+H]⁺.

Step 2: Synthesis of6-[2,7-diazaspiro[3.5]nonan-7-yl]pyridine-3-carbonitrile

A solution of tert-butyl7-(5-cyanopyridin-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (316 mg,0.96 mmol, 1 equiv) and TFA (1.5 mL) in DCM (7 mL) was stirred for 1 hat room temperature, and then the resulting solution was concentrated toafford 198 mg (90.14%) of the title compound as a light brown solid.LCMS (ESI, m/z): 229.14 [M+H]⁺.

Step 3: Synthesis of6-[2-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)-2,7-diazaspiro[3.5]nonan-7-yl]pyridine-3-carbonitrile

A solution of3-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxypropanoicacid (100 mg, 0.30 mmol, 1.20 equiv), HATU (100 mg, 0.26 mmol, 1.00equiv), DIPEA (66 mg, 0.51 mmol, 2.00 equiv) and6-[2,7-diazaspiro[3.5]nonan-7-yl]pyridine-3-carbonitrile (58 mg, 0.25mmol, 1.00 equiv) in DMF (15 mL) was stirred for 40 min at roomtemperature, and then the resulting solution was diluted with 20 ml ofH2O, extracted with 3×20 ml of EtOAc and the organic layer was combined,washed with 1×20 ml of brine and concentrated under vacuum, and then theresidue was purified by Prep-HPLC yielding the title compound (73.5 mg,53.0%) as a white solid. LCMS (ESI, m/z): 546.15 [M+H]⁺, ¹HNMR (CD3OD,300 MHz) δ 8.40 (d, J=2.4, 1H), 8.16 (s, 1H), 7.74 (dd, J=9.0, 2.4 Hz,1H), 6.90 (d, J=8.7 Hz, 1H), 4.61 (s, 1H), 3.92 (s, 2H), 3.80-3.61 (m,10H), 3.43 (dd, J=10.1, 7.7 Hz, 2H), 2.34 (t, J=6.0 Hz, 2H), 2.23 (t,J=5.4 Hz, 1H), 2.05-1.97 (m, 1H), 1.87-1.65 (m, 6H).

Example 106:(S)-6-(4-(3-((1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-1,4-diazepan-1-yl)nicotinonitrile

Step 1: Synthesis of Tert-Butyl4-(5-cyanopyridin-2-yl)-1,4-diazepane-1-carboxylate

A solution of tert-butyl 1,4-diazepane-1-carboxylate (1.5 g, 7.49 mmol,1.00 equiv), 6-chloropyridine-3-carbonitrile (1.174 g, 8.47 mmol, 1.05equiv), potassium carbonate (3.353 g, 24.26 mmol, 3.00 equiv) in NMP (20mL) was stirred for 1.5 h at 80° C. The resulting solution was quenchedwith 30 ml H₂O, extracted with EtOAc (3×30 mL) and the organic layerscombined. The solution was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (1:1) to afford 2 g (88%) ofthe title compound as a yellow oil. LCMS (ESI, m/z): 303.17 [M+H]⁺

Step 2: Synthesis of 6-(1,4-diazepan-1-yl)pyridine-3-carbonitrile

A solution of tert-butyl4-(5-cyanopyridin-2-yl)-1,4-diazepane-1-carboxylate (1 g, 3.31 mmol,1.00 equiv) in hydrogen chloride/dioxane (20 mL) was stirred for 1 h atroom temperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN to afford 225 mg(34%) of the title compound as a white solid. LCMS (ESI, m/z): 203.12[M+H]⁺

Step 3: Synthesis of(S)-6-(4-(3-((1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-1,4-diazepan-1-yl)nicotinonitrile

A solution of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicacid (100 mg, 0.30 mmol, 1.00 equiv),6-(1,4-diazepan-1-yl)pyridine-3-carbonitrile (72.72 mg, 0.36 mmol, 1.20equiv), HATU (171 mg, 0.45 mmol, 1.50 equiv), DIPEA (116.1 mg, 0.90mmol, 3.00 equiv) in DMF (3 mL) was stirred for 2 h at room temperature.After concentration, the residue was purified by Prep-HPLC eluting withH₂O/CH₃CN yielding the title compound (139 mg, 90%) as a white solid.LCMS (ESI, m/z): 520.15 [M+H]⁺, ¹HNMR (Methanol-d₄, 300 MHz) δ:8.41 (t,J=3.2 Hz, 1H), 8.11 (dd, J=7.1 Hz, 5.9 Hz, 1H), 7.74-7.71 (m, 1H), 6.79(dd, J=2.4 Hz, 2.7 Hz, 1H), 4.87 (s, 1H), 3.95 (t, J=5.8 Hz, 1H),3.89-3.63 (m, 9H), 3.62-3.50 (m, 2H), 3.49-3.37 (m, 2H), 2.55-2.54 (m,2H), 2.05 (s, 1H), 1.94-1.91 (m, 3H), 1.89-1.68 (m, 2H).

Example 107:6-[[1-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)azetidin-3-yl]amino]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl3-[(5-cyanopyridin-2-yl)amino]azetidine-1-carboxylate

A solution of tert-butyl 3-aminoazetidine-1-carboxylate (1 g, 5.81 mmol,1.00 equiv), potassium carbonate (1.6 g, 11.58 mmol, 2.00 equiv), and5-chloropyridin-2-carbonitrile (801 mg, 5.74 mmol, 1.00 equiv) in DMF(10 mL) was stirred for 2 h at 80° C. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (1/1)) to afford 300 mg (19%)of the title compound as colorless oil. LCMS (ESI, m/z): 275.32 [M+H]⁺

Step 2: Synthesis of 6-[(azetidin-3-yl)amino]pyridine-3-carbonitrileHydrochloride

A solution of tert-butyl3-[(5-cyanopyridin-2-yl)amino]azetidine-1-carboxylate (264 mg, 0.96mmol, 1.00 equiv) in hydrogen chloride/dioxane (10 mL) was stirred for 2h at 25° C. The solids were collected by filtration to afford 170 mg(crude) of the title compound as yellow solids. LCMS (ESI, m/z): 175.20[M+H]⁺

Step 3: Synthesis of6-[[1-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)azetidin-3-yl]amino]pyridine-3-carbonitrile

A solution of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicacid (100 mg, 0.30 mmol, 1.00 equiv), HATU (114 mg, 0.30 mmol, 1.00equiv), DIPEA (155 mg, 1.20 mmol, 4.00 equiv), and6-[(azetidin-3-yl)amino]pyridine-3-carbonitrile hydrochloride (74 mg,0.30 mmol, 1.00 equiv) in DMF (2 mL) was stirred for 1 h at 25° C. Thecrude product was purified by Flash-Prep yielding the title compound(94.7 mg, 65%) as white solids. LCMS (ESI, m/z): 492.20 [M+H]⁺, ¹H-NMR(CD₃OD, 400 MHz) δ: 8.36 (d, J=2.3 Hz, 1H), 8.14 (d, J=5.1 Hz, 1H), 7.65(dd, J=8.8, 2.3 Hz, 1H), 6.60 (d, J=8.8 Hz, 1H), 4.66 (d, J=7.6 Hz, 1H),4.58 (s, 1H), 4.47 (dt, J=16.5, 8.5 Hz, 1H), 4.29 (dt, J=17.8, 8.5 Hz,1H), 4.00 (d, J=5.0 Hz, 1H), 3.83 (dd, J=10.2, 5.1 Hz, 1H), 3.76-3.55(m, 2H), 3.48-3.33 (m, 1H), 2.33 (dd, J=14.9, 8.1 Hz, 1H), 2.45-2.20 (m,3H), 2.00-1.91 (m, 1H), 1.81-1.68 (m, 2H).

Example 108:6-[6-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)-2,6-diazaspiro[3.3]heptan-2-yl]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl6-(5-cyanopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

A solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (500mg, 2.52 mmol, 1.00 equiv), potassium carbonate (1.05 mg, 0.01 mmol,3.00 equiv), 6-chloropyridine-3-carbonitrile (383.3 mg, 2.77 mmol, 1.10equiv) in DMF (10 mL) was stirred for 2 h at 100° C. The resultingsolution was quenched with 50 ml water. Then the solution was extractedwith (3×50 mL) EtOAc and the organic layers combined. The residue wasapplied onto a silica gel column eluting with EtOAc/hexane (50:50) toafford 360 mg (48%) of the title compound as a yellow solid. LCMS (ESI,m/z): 301.17 [M+H]+

Step 2: Synthesis of6-[2,6-diazaspiro[3.3]heptan-2-yl]pyridine-3-carbonitrile

A solution of tert-butyl6-(5-cyanopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (300mg, 1.00 mmol, 1.00 equiv), TFA (2 mL) in DCM (10 mL) was stirred for 1h at room temperature. The resulting mixture was concentrated undervacuum to afford 180 mg crude of the title compound as a white solid.LCMS (ESI, m/z): 201.12 [M+H]⁺

Step 3: Synthesis of6-[6-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)-2,6-diazaspiro[3.3]heptan-2-yl]pyridine-3-carbonitrile

A solution of 6-[2,6-diazaspiro[3.3]heptan-2-yl]pyridine-3-carbonitrile(100 mg, 0.50 mmol, 1.00 equiv), HATU (136 mg, 0.36 mmol, 1.20 equiv),DIPEA (115 mg, 0.89 mmol, 3.00 equiv),3-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxypropanoicacid (72 mg, 0.21 mmol, 1.20 equiv) in DMF (3 mL) was stirred for 2 h atroom temperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN. Then the residuewas further purified by Prep-HPLC yielding the title compound (42.7 mg,17%) as a white solid. LCMS (ESI, m/z): 518.10 [M+H]+, ¹H NMR (300 MHz,Methanol-d4) δ 8.37 (s, 1H), 8.17 (s, 1H), 7.74 (dd, J=8.8, 2.2 Hz, 1H),6.48 (dd, J=8.9, 0.8 Hz, 1H), 4.61 (q, J=7.8, 3.3 Hz, 1H), 4.41-4.21 (m,6H), 4.17 (s, 2H), 3.86-3.54 (m, 4H), 3.49-3.33 (m, 1H), 3.33-3.31 (m,1H), 2.33-2.22 (m, 3H), 2.02-1.98 (m, 1H), 1.77-1.65 (m, 2H).

Example 109:6-[2-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)-2,6-diazaspiro[3.4]octan-6-yl]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl6-(5-cyanopyridin-2-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate

A solution of tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (300mg, 1.41 mmol, 1.00 equiv), 6-chloropyridine-3-carbonitrile (390 mg,2.81 mmol, 2.00 equiv) and K₂CO₃ (390 mg, 2.82 mmol, 2.00 equiv) in NMP(10 mL) was stirred for 4 h at 80° C., and then the resulting solutionwas diluted with 200 mL of H₂O, extracted with 3×50 mL of EtOAc and theorganic layers combined, washed with 1×50 mL of brine, dried overanhydrous sodium sulfate and concentrated under vacuum, and then theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (40/60) to afford 380 mg (86%) of the titlecompound as a yellow solid. LCMS (ESI, m/z): 315.17 [M+H]⁺.

Step 2: Synthesis of6-[2,6-diazaspiro[3.4]octan-6-yl]pyridine-3-carbonitrile

A solution of tert-butyl6-(5-cyanopyridin-2-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (360 mg,1.15 mmol, 1.00 equiv) and TFA (4 mL) in DCM (20 mL) was stirred for 2 hat room temperature, and then the resulting solution was concentratedunder vacuum to afford 730 mg of the title compound as a yellow solid.LCMS (ESI, m/z): 215.12 [M+H]⁺.

Step 3: Synthesis of6-[2-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)-2,6-diazaspiro[3.4]octan-6-yl]pyridine-3-carbonitrile

A solution of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicacid (100 mg, 0.30 mmol, 1.00 equiv), HATU (113 mg, 0.30 mmol, 1.00equiv), DIPEA (116 mg, 0.90 mmol, 3.00 equiv) and6-2,6-diazaspiro[3.4]octan-6-ylpyridine-3-carbonitrile (96 mg, 0.45mmol, 1.50 equiv) in DMF (8 mL) was stirred for 2 h at room temperature,and then the resulting solution was diluted with 30 mL of H₂O, extractedwith 3×30 mL of EtOAc and the organic layers combined, washed with 2×30mL of brine, dried over anhydrous sodium sulfate and concentrated undervacuum, and then the residue was purified by Prep-HPLC yielding thetitle compound (22.6 mg, 14%) as a white solid. LCMS (ESI, m/z): 532.10[M+H]+, ¹H NMR (DMSO-d₆, 400 MHz) δ 12.36 (s, 1H), 8.47 (d, J=2.0 Hz,1H), 8.02 (s, 1H), 7.84 (dd, J=9.0, 2.3 Hz, 1H), 6.56 (dd, J=8.8, 2.4Hz, 1H), 4.53 (s, 1H), 4.06 (dd, J=8.4, 3.8 Hz, 1H), 3.99 (d, J=9.3 Hz,1H), 3.82-3.77 (m, 2H), 3.68-3.49 (m, 8H), 3.38-3.36 (m, 1H), 3.24-3.19(m, 1H), 2.27-2.07 (m, 5H), 1.89 (d, J=5.2 Hz, 1H), 1.65 (dd, J=17.2,5.9 Hz, 2H).

Example 110:6-[4-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)-octahydropyrrolo[3,2-b]pyrrol-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl4-(5-cyanopyridin-2-yl)-octahydropyrrolo[3,2-b]pyrrole-1-carboxylate

A solution of tert-butyl octahydropyrrolo[3,2-b]pyrrole-1-carboxylate(200 mg, 0.94 mmol, 1.00 equiv), 6-chloropyridine-3-carbonitrile (260mg, 1.88 mmol, 2.00 equiv) and K₂CO₃ (260 mg, 1.88 mmol, 2.00 equiv) inNMP (10 mL) was stirred for 2 h at 80° C., and then the resultingsolution was diluted with 200 mL of H2O, extracted with 3×50 mL of EtOAcand the organic layers combined, washed with 1×50 mL of brine, driedover anhydrous sodium sulfate and concentrated under vacuum, and thenthe residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (2:3) to afford 284 mg (96%) of the title compoundas light yellow oil. LCMS (ESI, m/z): 315.18[M+H]⁺.

Step 2: Synthesis of6-[octahydropyrrolo[3,2-b]pyrrol-1-yl]pyridine-3-carbonitrile

A solution of tert-butyl4-(5-cyanopyridin-2-yl)-octahydropyrrolo[3,2-b]pyrrole-1-carboxylate(238 mg, 0.76 mmol, 1.00 equiv) and TFA (1 mL) in DCM (5 mL) was stirredfor 1 h at room temperature, and then the resulting solution wasconcentrated under vacuum to afford 150 mg of the title compound as acrude yellow oil. LCMS (ESI, m/z): 215.13 [M+H]⁺.

Step 3: Synthesis of6-[4-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)-octahydropyrrolo[3,2-b]pyrrol-1-yl]pyridine-3-carbonitrile

A solution of3-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxypropanoicacid (100 mg, 0.30 mmol, 1.50 equiv), HATU (113 mg, 0.30 mmol, 1.00equiv), DIPEA (77 mg, 0.60 mmol, 2.00 equiv) and6-[octahydropyrrolo[3,2-b]pyrrol-1-yl]pyridine-3-carbonitrile (100 mg,0.47 mmol, 1.00 equiv) in DMF (10 mL) was stirred for 40 min at roomtemperature, and then the resulting solution was diluted with 20 ml ofH₂O, extracted with 3×20 ml of EtOAc and the organic layer was combined,washed with 1×20 ml of brine and concentrated under vacuum, and then theresidue was purified by Prep-HPLC yielding the title compound (46.7 mg,19.0%) as a white solid. LCMS (ESI, m/z): 532.10 [M+H]+, ¹HNMR (CD3OD,300 MHz) δ 8.43 (d, J=1.5 Hz, 1H), 8.15 (d, J=1.8 Hz, 1H), 7.78 (dt,J=8.9, 2.5 Hz, 1H), 6.67 (d, J=9.6 Hz, 1H), 4.70-4.62 (m, 3H), 3.78-3.36(m, 10H), 2.59 (t, J=2.1 Hz, 2H), 2.40-1.97 (m, 6H), 1.82-1.69 (m, 2H).

Example 111:6-[7-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)-2,7-diazaspiro[4.4]nonan-2-yl]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl7-(5-cyanopyridin-2-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

A solution of 6-chloropyridine-3-carbonitrile (610 mg, 4.40 mmol, 1.00equiv), potassium carbonate (1.2 g, 8.68 mmol, 3.00 equiv), tert-butyl2,7-diazaspiro[4.4]nonane-2-carboxylate (1 g, 4.42 mmol, 1.00 equiv) inDMF (30 mL) was stirred for 2 h at 80° C. The resulting solution wasquenched with 30 ml water. Then the solution was extracted with EtOAc(3×30 mL) and the organic layers combined. The residue was applied ontoa silica gel column with EtOAc/petroleum ether (1:4) to afford 1.2 g(83.1%) of the title compound as a white solid. LCMS (ESI, m/z): 329.20[M+H]⁺

Step 2: Synthesis of6-[2,7-diazaspiro[4.4]nonan-2-yl]pyridine-3-carbonitrile

A solution of tert-butyl7-(5-cyanopyridin-2-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (118 mg,0.36 mmol, 1.00 equiv) in hydrogen chloride/dioxane (5 mL) was stirredfor 20 min at room temperature. The resulting mixture was concentratedunder vacuum to afford 100 mg crude of the title compound as yellow oil.LCMS (ESI, m/z): 229.14 [M+H]⁺

Step 3: Synthesis of6-[7-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)-2,7-diazaspiro[4.4]nonan-2-yl]pyridine-3-carbonitrile

A solution of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicacid (100 mg, 0.30 mmol, 1.00 equiv), HATU (148 mg, 0.39 mmol, 1.30equiv), DIEA (77.4 mg, 0.60 mmol, 2.00 equiv),6-[2,7-diazaspiro[4.4]nonan-2-yl]pyridine-3-carbonitrile (82 mg, 0.36mmol, 1.20 equiv) in DMF (5 mL) was stirred for 2 h at room temperature.After concentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN yielding the title compound (75.1mg, 46%) as a white solid. LCMS (ESI, m/z): 546.20 [M+H]⁺, ¹H NMR (300MHz, Chloroform-d) δ 8.39 (s, 1H), 8.13 (dd, J=2.4, 0.8 Hz, 1H), 7.73(dd, J=8.7, 2.4 Hz, 1H), 6.59 (dd, J=8.7, 0.8 Hz, 1H), 4.71-4.45 (m,1H), 3.93-3.74 (m, 1H), 3.74-3.61 (m, 6H), 3.57-3.49 (m, 4H), 3.48-3.39(m, 3H), 2.53-2.50 (m, 2H), 2.26-2.14 (m, 1H), 2.11-1.92 (m, 5H),1.83-1.53 (m, 2H).

Example 112:6-((1S,4S)-5-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-2,5-diaza-bicyclo[2.2.1]heptan-2-yl)nicotinonitrileand6-((1R,4R)-5-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-2,5-diaza-bicyclo[2.2.1]heptan-2-yl)nicotinonitrile

Step 1: Synthesis of Tert-Butyl5-(5-cyanopyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

A solution of tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(600 mg, 3.03 mmol, 1.00 equiv), 6-chloropyridine-3-carbonitrile (460mg, 3.32 mmol, 1.10 equiv), potassium carbonate (1.254 g, 17.16 mmol,3.00 equiv) in DMF (10 mL) was stirred for 1.5 h at 80° C. The resultingsolution was quenched with 40 ml water. The solution was extracted withEtOAc (3×40 mL) and the organic layers combined. The solution was driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas applied onto a silica gel column eluting with EtOAc/hexane (1:1) toafford 770 mg (85%) of the title compound as a yellow solid. LCMS (ESI,m/z): 301.16 [M+H]⁺

Step 2: Synthesis of6-[2,5-diazabicyclo[2.2.2.]heptan-2-yl]pyridine-3-carbonitrile

A solution of tert-butyl5-(5-cyanopyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(740 mg, 2.46 mmol, 1.00 equiv) in hydrogen chloride/dioxane (15 mL) wasstirred for 0.5 h at room temperature. The resulting mixture wasconcentrated under vacuum to afford 480 mg crude of the title compoundas a light yellow solid. LCMS (ESI, m/z): 201.11 [M+H]⁺

Step 3: Synthesis of6-((1S,4S)-5-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-2,5-diaza-bicyclo[2.2.2.1]heptan-2-yl)nicotinonitrileand6-((1R,4R)-5-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-2,5-diaza-bicyclo[2.2.1]heptan-2-yl)nicotinonitrile

A solution of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicacid (100 mg, 0.30 mmol, 1.00 equiv),6-[2,5-diazabicyclo[2.2.1]heptan-2-yl]pyridine-3-carbonitrile (72 mg,0.36 mmol, 1.20 equiv), HATU (171 mg, 0.45 mmol, 1.50 equiv), DIEA(116.1 mg, 0.90 mmol, 3.00 equiv) in DMF (3 mL) was stirred for 1.5 h atroom temperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN. Then the residuewas further purified by Prep-HPLC and Chiral-Prep-HPLC yielding (afterarbitrary assignment of the stereochemistry) the title compounds,respectively, as white solids, isomer A (11.4 mg, 20%) LCMS (ESI, m/z):518.15 [M+H]⁺, ¹HNMR (Methanol-d₄, 300 MHz) δ: 8.39 (s, 1H), 8.07 (d,J=14.4 Hz, 1H), 7.74 (d, J=8.9 Hz, 1H), 6.61 (s, 1H), 5.07-4.95 (m, 2H),4.80 (s, 1H), 4.69-4.42 (m, 1H), 3.95-3.30 (m, 9H), 2.69 (d, J=15 Hz,1H), 2.41 (s, 1H), 2.33-2.06 (m, 4H), 1.97 (d, J=10.0 Hz, 2H). tR=5.199min (CHIRAL Cellulose-SB, 0.46*10 cm; 3 um, Hex(20mMNH3):EtOH=60:40, 1.0mL/min) and isomer B (19 mg, 20%) LCMS (ESI, m/z): 518.15 [M+H]⁺,tR=6.858 min ((CHIRAL Cellulose-SB, 0.46*10 cm; 3 um,Hex(20mMNH3):EtOH=60:40, 1.0 mL/min)

Example 113:(S)-6-[5-(3-[[1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)-octahydropyrrolo[3,4-c]pyrrol-2-yl]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl5-(5-cyanopyridin-2-yl)-octahydropyrrolo[3,4-c]pyrrole-2-carboxylate

A solution of tert-butyl octahydropyrrolo[3,4-c]pyrrole-2-carboxylate (1g, 4.71 mmol, 1.00 equiv), 6-chloropyridine-3-carbonitrile (650 mg, 4.69mmol, 1.00 equiv), potassium carbonate (1.3 g, 9.41 mmol, 2.00 equiv),NMP (20 mL). The resulting solution was stirred for 1 h at 80° C. Theresulting solution was extracted with 100 mL of EtOAc and the organiclayers combined and concentrated under vacuum to afforded 1.1 g (74%) ofthe title compound as yellow oil. LCMS (ESI, m/z): 315.25 [M+H]⁺

Step 2: Synthesis of6-[octahydropyrrolo[3,4-c]pyrrol-2-yl]pyridine-3-carbonitrile HydrogenChloride

A solution of tert-butyl5-(5-cyanopyridin-2-yl)-octahydropyrrolo[3,4-c]pyrrole-2-carboxylate(860 mg, 2.74 mmol, 1.00 equiv), dioxane/HCl (10 mL). The resultingsolution was stirred for 1 h at 25° C. The solids were filtered out. Theresulting mixture was concentrated under vacuum to afforded 500 mg (85%)of the title compound as yellow oil. LCMS (ESI, m/z): 215.22 [M+H]⁺

Step 3: Synthesis of(S)-6-[5-(3-[[1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)-octahydropyrrolo[3,4-c]pyrrol-2-yl]pyridine-3-carbonitrile

A solution of(S)-3-[[1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicacid (170 mg, 0.51 mmol, 1.00 equiv),6-[octahydropyrrolo[3,4-c]pyrrol-2-yl]pyridine-3-carbonitrile hydrogenchloride (200 mg, 0.93 mmol, 1.00 equiv), HATU (190 mg, 0.50 mmol, 1.00equiv), DIEA (1 mL), DMF (4 mL). The resulting solution was stirred for1 h at 25° C. The crude product was purified by Flash-Prep-HPLC yieldingthe title compound (49.3 mg, 18%) as a white solid. LCMS (ESI, m/z):510.15 [M+H]⁺, ¹HNMR (DMSO-d₆, 400 MHz) δ: 12.35 (s, 1H), 8.47 (s, 1H),8.00 (d, J=4.0 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 6.54 (d, J=5.2 Hz, 1H),4.49-4.51 (m, 1H), 4.01-3.46 (m, 12H), 3.26-3.20 (m, 2H), 3.11-2.90 (m,2H), 2.46-2.38 (m, 2H), 2.10-2.03 (m, 1H), 1.92-1.88 (m, 1H), 1.65-1.78(m, 2H). tR=2.648 min (XBridge Prep OBD C18 Column 30*150 mm 5 um Water(NH₄HCO₃):CH₃CN=70:30, 1.0 mL/min)

Example 114:N-[1-(5-cyanopyridin-2-yl)piperidin-3-yl]-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanamide

Step 1: Synthesis of Tert-ButylN-[1-(5-cyanopyridin-2-yl)piperidin-4-yl]carbamate

A solution of 6-chloropyridine-3-carbonitrile (690 mg, 4.98 mmol, 1.00equiv), potassium carbonate (1.38 g, 9.98 mmol, 2.00 equiv), tert-butylN-(piperidin-4-yl)carbamate (1 g, 4.99 mmol, 1.00 equiv) in DMF (20 mL)was stirred for 1 h at 80° C. The resulting solution was quenched with30 ml water. Then the solution was extracted with EtOAc (3×30 mL) andthe organic layers combined. The residue was applied onto a silica gelcolumn with EtOAc/petroleum ether (2:3) to afford 1.5 g (99%) of thetitle compound as a white solid. LCMS (ESI, m/z): 303.18 [M+H]⁺

Step 2: Synthesis of 6-(3-aminopiperidin-1-yl)pyridine-3-carbonitrile

A solution of tert-butylN-[1-(5-cyanopyridin-2-yl)piperidin-3-yl]carbamate (118 mg, 0.39 mmol,1.00 equiv) in hydrogen chloride/dioxane (10 mL) was stirred for 30 minat room temperature. The resulting mixture was concentrated under vacuumto afford 79 mg crude of the title compound as a white solid. LCMS (ESI,m/z): 203.13 [M+H]⁺

Step 3: Synthesis ofN-[1-(5-cyanopyridin-2-yl)piperidin-3-yl]-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanamide

A solution of3-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxypropanoicacid (100 mg, 0.30 mmol, 1.00 equiv), HATU (147 mg, 0.39 mmol, 1.30equiv), DIEA (155 mg, 1.20 mmol, 4.00 equiv),6-(3-aminopiperidin-1-yl)pyridine-3-carbonitrile (79 mg, 0.39 mmol, 1.30equiv) in DMF (10 mL) was stirred for 1 h at room temperature. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN. Then the residue was furtherpurified by Prep-HPLC yielding the title compound (72.2 mg, 47%) as awhite solid. LCMS (ESI, m/z): 520.15 [M+H]⁺, ¹H NMR (300 MHz,Methanol-d₄) δ 8.36 (s, 1H), 8.11 (s, 1H), 7.69 (dd, J=9.1, 2.4 Hz, 1H),6.86-6.83 (m, 1H), 4.61-4.48 (m, 1H), 4.23-4.05 (m, 2H), 3.85-3.57 (m,5H), 3.46-3.39 (m, 2H), 3.29-3.12 (m, 1H), 3.11-3.02 (m, 1H), 2.37 (t,J=6.0 Hz, 2H), 2.29-2.10 (m, 1H), 2.05-1.92 (m, 2H), 1.90-1.85 (m, 1H),1.78-1.68 (m, 2H), 1.62-1.56 (m, 2H).

Example 115:N-[1-(5-cyanopyridin-2-yl)piperidin-4-yl]-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanamide

Step 1: Synthesis of Tert-ButylN-[1-(5-cyanopyridin-2-yl)piperidin-4-yl]carbamate

A solution of 6-chloropyridine-3-carbonitrile (1 g, 7.22 mmol, 1.00equiv), potassium carbonate (2 g, 14.47 mmol, 2.00 equiv), tert-butylN-(piperidin-4-yl)carbamate (1.45 g, 7.24 mmol, 1.00 equiv) in DMF (20mL) was stirred for 1.5 h at 80° C. The resulting solution was quenchedwith 30 ml water. The solution was extracted with EtOAc (3×30 mL) andthe organic layers combined. The solution was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with EtOAc/petroleum ether (2:3) to afford 1.7g (78%) of the title compound as a white solid. LCMS (ESI, m/z):303.18[M+H]⁺

Step 2: Synthesis of 6-(4-aminopiperidin-1-yl)pyridine-3-carbonitrile

A solution of tert-butylN-[1-(5-cyanopyridin-2-yl)piperidin-4-yl]carbamate (118 mg, 0.39 mmol,1.00 equiv) in hydrogen chloride/dioxane (10 mL) was stirred for 30 minat room temperature. The resulting mixture was concentrated under vacuumto afford 79 mg crude of the title compound as a white solid. LCMS (ESI,m/z): 203.13 [M+H]⁺

Step 3: Synthesis ofN-[1-(5-cyanopyridin-2-yl)piperidin-4-yl]-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanamide

A solution of 6-(4-aminopiperidin-1-yl)pyridine-3-carbonitrile (79 mg,0.39 mmol, 1.00 equiv), HATU (148 mg, 0.39 mmol, 1.30 equiv), DIEA (155mg, 1.20 mmol, 2.00 equiv),3-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxypropanoicacid (100 mg, 0.30 mmol, 1.30 equiv) in DMF (10 mL) was stirred for 1 hat room temperature. After concentration, the residue was purified byC18 reverse phase chromatography eluting with H₂O/CH₃CN. Then theresidue was further purified by Prep-HPLC yielding the title compound(74.2 mg, 37%) as a white solid. LCMS (ESI, m/z): 520.30 [M+H]⁺, ¹H NMR(300 MHz, Methanol-d₄) δ 8.39 (s, 1H), 8.14 (s, 1H), 7.72 (dd, J=9.1,2.4 Hz, 1H), 6.88 (dd, J=9.2, 0.8 Hz, 1H), 4.58-4.50 (m, 1H), 4.45-4.35(m, 2H), 4.01-3.88 (m, 1H), 3.75-3.60 (m, 4H), 3.47-3.34 (m, 2H), 3.12(t, J=11.7 Hz, 2H), 2.38 (t, J=5.8 Hz, 2H), 2.26-2.15 (m, 1H), 2.05-1.92(m, 3H), 1.80-1.60 (m, 2H), 1.46-1.30 (m, 2H).

Example 116:6-[[1-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)piperidin-4-yl]amino]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl4-[(5-cyanopyridin-2-yl)amino]piperidine-1-carboxylate

A solution of 6-chloropyridine-3-carbonitrile (760 mg, 5.49 mmol, 1.00equiv), potassium carbonate (1.52 g, 11.0 mmol, 2.00 equiv), tert-butyl4-aminopiperidine-1-carboxylate (1.1 g, 5.49 mmol, 1.00 equiv) in DMF(20 mL) was stirred for 1.5 h at 80° C. The resulting solution wasquenched with 50 ml water. The solution was extracted with EtOAc (3×50mL) and the organic layers combined. The solution was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column with EtOAc/petroleum ether (2:3) toafford 460 mg (28%) of the title compound as a yellow solid. LCMS (ESI,m/z): 303.18 [M+H]⁺

Step 2: Synthesis of 6-[(piperidin-4-yl)amino]pyridine-3-carbonitrile

A solution of tert-butyl4-[(5-cyanopyridin-2-yl)amino]piperidine-1-carboxylate (118 mg, 0.39mmol, 1.00 equiv) in hydrogen chloride/dioxane (10 mL) was stirred for30 min at room temperature. The resulting mixture was concentrated undervacuum to afford 79 mg crude of the title compound as a white solid.LCMS (ESI, m/z): 203.13 [M+H]⁺

Step 3: Synthesis of6-[[1-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)piperidin-4-yl]amino]pyridine-3-carbonitrile

A solution of 6-[(piperidin-4-yl)amino]pyridine-3-carbonitrile (79 mg,0.39 mmol, 1.30 equiv), HATU (148 mg, 0.39 mmol, 1.30 equiv), DIEA (155mg, 1.20 mmol, 2.00 equiv),3-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxypropanoicacid (100 mg, 0.30 mmol, 1.00 equiv) in DMF (2 mL) was stirred for 1 hat room temperature. After concentration, the residue was purified byC18 reverse phase chromatography eluting with H₂O/CH₃CN. Then theresidue was further purified by Prep-HPLC yielding the title compound(43.9 mg, 28%) as a white solid. LCMS (ESI, m/z): 520.15 [M+H]⁺, ¹H NMR(300 MHz, Methanol-d₄) δ 8.33 (s, 1H), 8.14 (s, 1H), 7.60 (dd, J=8.9,2.3 Hz, 1H), 6.56 (dd, J=8.9, 0.8 Hz, 1H), 4.63-4.52 (m, 1H), 4.42 (d,J=13.5 Hz, 1H), 4.18-4.02 (m, 1H), 3.98-3.86 (m, 1H), 3.81-3.60 (m, 4H),3.49-3.38 (m, 2H), 3.22 (t, J=12.3 Hz, 1H), 2.88 (q, J=12.1, 11.6 Hz,1H), 2.72-2.48 (m, 2H), 2.24-2.12 (m, 1H), 2.10-2.03 (m, 1H), 2.02-1.98(m, 2H), 1.82-1.64 (m, 2H), 1.50-1.42 (m, 2H).

Example 117:N-[1-(5-cyanopyridin-2-yl)pyrrolidin-3-yl]-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanamide

Step 1: Synthesis of Tert-ButylN-[1-(5-cyanopyridin-2-yl)pyrrolidin-3-yl]carbamate

A solution of tert-butyl N-(pyrrolidin-3-yl)carbamate (1 g, 5.37 mmol,1.00 equiv), potassium carbonate (1.5 g, 10.85 mmol, 2.00 equiv),6-chloropyridine-3-carbonitrile (742 mg, 5.36 mmol, 1.00 equiv) in DMF(10 mL) was stirred for 1 h at 80° C. The resulting solution wasquenched with 40 ml water. The solution was extracted with EtOAc (3×40mL) and the organic layers combined. The solution was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column eluting with EtOAc/hexane (4:1) toafford 1.37 g (88%) of the title compound as a white solid. LCMS (ESI,m/z): 289.17 [M+H]⁺

Step 2: Synthesis of 6-(3-aminopyrrolidin-1-yl)pyridine-3-carbonitrile

A solution of tert-butylN-[[1-(5-cyanopyridin-2-yl)pyrrolidin-3-yl]methyl]carbamate (112 mg,0.37 mmol, 1 equiv) in HCl/dioxane (10 mL) was stirred for 40 min atroom temperature. The solvent was concentrated under vacuum to afford 73mg crude of the title compound as a white solid. LCMS (ESI, m/z): 189.11[M+H]⁺

Step 3: Synthesis ofN-[1-(5-cyanopyridin-2-yl)pyrrolidin-3-yl]-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanamide

A solution of3-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxypropanoicacid (100 mg, 0.30 mmol, 1.00 equiv), HATU (148 mg, 0.39 mmol, 1.30equiv), DIEA (155 mg, 1.20 mmol, 4.00 equiv),6-(3-aminopyrrolidin-1-yl)pyridine-3-carbonitrile (73 mg, 0.39 mmol,1.30 equiv) in DMF (3 mL) was stirred for 1 h at room temperature. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN yielding the title compound (59.6mg, 40%) as a white solid. LCMS (ESI, m/z): 506.15 [M+H]⁺, ¹H NMR (300MHz, Methanol-d₄) δ 8.39 (s, 1H), 8.12 (s, 1H), 7.73 (dd, J=8.9, 2.3 Hz,1H), 6.58 (dd, J=8.9, 0.8 Hz, 1H), 4.59-4.42 (m, 2H), 3.92-3.59 (m, 7H),3.6-3.32 (m, 3H), 2.39 (t, J=6.3 Hz, 2H), 2.27-2.12 (m, 2H), 2.10-1.92(m, 2H), 1.72-1.58 (m, 2H).

Example 118:6-[4-(3,3-dimethyl-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of6-[4-(4-hydroxy-3,3-dimethylbutanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of Int-A4 (1.56 g, 5.97 mmol, 1.00 equiv),4,4-dimethyloxolan-2-one (2.05 g, 18.0 mmol, 3.00 equiv), and Al(CH₃)₃(12 mL, 2.00 equiv) in toluene (5 mL) was stirred overnight at 70° C.The reaction mixture was diluted with DCM (50 mL). The resulting mixturewas washed with 2×15 mL of saturated sodium chloride aqueous solution.The resulting mixture was concentrated under vacuum. The residue wasapplied onto a silica gel column with DCM/methanol (1/1) to afford 1.17g (65%) of the title compound as a white solid. LCMS (ESI, m/z): 303.37[M+H]⁺

Step 2: Synthesis of Tert-Butyl(2S)-2-([4-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-2,2-dimethyl-4-oxobutoxy]methyl)pyrrolidine-1-carboxylate

A solution of6-[4-(4-hydroxy-3,3-dimethylbutanoyl)piperazin-1-yl]pyridine-3-carbonitrile(970 mg, 3.21 mmol, 1.00 equiv), sodium hydride (140 mg, 5.83 mmol, 1.10equiv), and tert-butyl(2S)-2-[(methanesulfonyloxy)methyl]pyrrolidine-1-carboxylate (896 mg,3.21 mmol, 1.00 equiv) in DMF (15 mL) was stirred for 3 days 50° C. Thereaction mixture was diluted with H₂O (200 mL). The resulting solutionwas extracted with 3×150 mL of EtOAc, and the organic layers combinedand concentrated under vacuum. The residue was applied onto a silica gelcolumn with EtOAc/petroleum ether (4/6) to afford 125 mg (8%) of thetitle compound as brown oil. LCMS (ESI, m/z): 486.62 [M+H]⁺

Step 3: Synthesis of6-[4-(3,3-dimethyl-4-[[(2S)-pyrrolidin-2-yl]methoxy]butanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of tert-butyl(2S)-2-([4-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-2,2-dimethyl-4-oxobutoxy]methyl)pyrrolidine-1-carboxylate(125 mg, 0.26 mmol, 1.00 equiv), and a solution of hydrogenchloride/dioxane (5 mL) in dioxane (5 mL) was stirred for 0.5 h at 25°C. The resulting mixture was concentrated under vacuum to afford 99 mg(100%) of the title compound as yellow oil. LCMS (ESI, m/z): 386.50[M+H]⁺

Step 4: Synthesis of6-[4-(3,3-dimethyl-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-(3,3-dimethyl-4-[[(2S)-pyrrolidin-2-yl]methoxy]butanoyl)piperazin-1-yl]pyridine-3-carbonitrile(99 mg, 0.26 mmol, 1.00 equiv), Int-A6 (85 mg, 0.26 mmol, 1.00 equiv),and TEA (78 mg, 0.77 mmol, 3.00 equiv) in EtOH (2 mL) was stirred for 1h at 60° C. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with petroleum ether/EtOAc(1/19) to afford 118 mg (68%) of the title compound as yellow oil. LCMS(ESI, m/z): 678.83 [M+H]⁺

Step 5: Synthesis of6-[4-(3,3-dimethyl-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-(3,3-dimethyl-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoyl)piperazin-1-yl]pyridine-3-carbonitrile(118 mg, 0.17 mmol, 1.00 equiv) in TFA/DCM (12 mL) was stirred for 1 hat 25° C. The pH value of the solution was adjusted to 8-9 withNH₂CH₂CH₂OH. The resulting mixture was washed with 2×100 mL of H₂O. Themixture was dried over anhydrous sodium sulfate. After concentration,the residue was purified by C18 reverse phase chromatography elutingwith H₂O/CH₃CN yielding the title compound 60.3 mg (63%) as whitesolids. LCMS (ESI, m/z): 548.57 [M+H]⁺, ¹H-NMR (400 MHz, Methanol-d₄) δ:8.45 (d, J=2.0 Hz, 1H), 8.23 (s, 1H), 7.79-7.77 (m, 1H), 6.90-6.88 (d,J=8.8 Hz, 1H), 4.71-4.69 (d, J=5.2 Hz, 1H), 3.75-3.62 (m, 10H),3.43-3.33 (m, 3H), 3.23-3.21 (m, 1H), 2.34 (s, 2H), 2.29-2.20 (m, 1H),2.15-2.03 (m, 1H), 1.81-1.73 (m, 2H), 0.97 (d, J=17.2 Hz, 6H).

Example 119:6-[4-(4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-2-ynoyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl(2S)-2-[(prop-2-yn-1-yloxy)methyl]pyrrolidine-1-carboxylate

To a solution of tert-butyl(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (5 g, 24.84 mmol, 1.00equiv) in THF (100 mL) was added sodium hydride (2 g, 83.33 mmol, 2.00equiv) in several batches at 0° C. over 15 min. To this was added3-bromoprop-1-yne (8.8 g, 73.97 mmol, 3.00 equiv) dropwise with stirringat 0° C. The resulting solution was stirred for 1 h at room temperature.The reaction was then quenched by the addition 50 mL of water. Theresulting solution was extracted with 3×100 mL of EtOAc and the organiclayers combined and dried over anhydrous sodium sulfate. Afterconcentration, the residue was applied onto a silica gel column elutingwith EtOAc/petroleum ether (1:15) to afford 5.3 g (89%) of the titlecompound as light yellow oil. LCMS (ESI, m/z): 240.15 [M+H]⁺

Step 2: Synthesis of 2-[(prop-2-yn-1-yloxy)methyl]pyrrolidine

A solution of tert-butyl2-[(prop-2-yn-1-yloxy)methyl]pyrrolidine-1-carboxylate (2.5 g, 10.45mmol, 1.00 equiv) in hydrogen chloride/dioxane (30 mL) was stirred for30 min at room temperature. The resulting mixture was concentrated undervacuum to afford 2 g crude of the title compound as yellow oil. LCMS(ESI, m/z): 140.10 [M+H]⁺

Step 3: Synthesis of5-[(2S)-2-[(prop-2-yn-1-yloxy)methyl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of (2S)-2-[(prop-2-yn-1-yloxy)methyl]pyrrolidinehydrochloride (2 g, 11.39 mmol, 1.00 equiv), TEA (3.4 g, 33.60 mmol,3.00 equiv), Int-A6 (4.48 g, 13.63 mmol, 1.20 equiv) in ethanol (40 mL)was stirred for 1 h at 60° C. in an oil bath. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (5:95) to afford 3 g (61%) ofthe title compound as a red oil. LCMS (ESI, m/z): 432.19 [M+H]⁺

Step 4: Synthesis of4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-2-ynoicAcid

To a solution of5-[(2S)-2-[(prop-2-yn-1-yloxy)methyl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(2 g, 4.63 mmol, 1.00 equiv) in THF (100 mL) was added n-BuLi (2.24 mL,1.20 equiv) dropwise with stirring at −70° C. The mixture was stirredfor 20 min at −70 degrees C. To this was added CO₂ (2 g, 10.00 equiv) inseveral batches at −70° C. The resulting solution was stirred for 20 minat room temperature. The pH value of the solution was adjusted to 6 withhydrogen chloride (2 M). The resulting solution was extracted with 3×100mL of DCM and the organic layers combined and dried over anhydroussodium sulfate and concentrated under vacuum. The crude product waspurified by C18 reverse phase column eluting with ACN/water to afford1.4 g (64%) of the title compound as an off-white solid. LCMS (ESI,m/z): 476.18 [M+H]⁺

Step 5: Synthesis of6-[4-(4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-2-ynoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of Int-A4 (600 mg, 2.67 mmol, 1.00 equiv),4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-2-ynoicacid (340 mg, 0.71 mmol, 1.20 equiv), DIEA (488 mg, 3.78 mmol, 3.00equiv), HATU (720 mg, 1.89 mmol, 1.50 equiv) in DMF (5 mL) was stirredfor 2 h at room temperature. The crude product was purified by C18reverse phase column eluting with ACN/H2O to afford 750 mg (43%) of thetitle compound as an off-white solid. LCMS (ESI, m/z): 646.27 [M+H]⁺

Step 6: Synthesis of6-[4-(4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-2-ynoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-(4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-2-ynoyl)piperazin-1-yl]pyridine-3-carbonitrile(200 mg, 0.31 mmol, 1.00 equiv), TFA (2 mL) in DCM (20 mL) was stirredfor 1 h at room temperature. The pH value of the solution was adjustedto 8 with ethanolamine. The resulting solution was extracted with 3×100mL of DCM and the organic layers combined and dried over anhydroussodium sulfate. After concentration, the residue was purified by C18reverse phase column eluting with ACN/water yielding the title compound(73.1 mg, 46%) as a white solid. LCMS (ESI, m/z): 516.19 [M+H]⁺, ¹HNMR(DMSO-d₆, 400 MHz) δ: 12.41 (s, 1H), 8.56-8.51 (m, 1H), 8.07 (s, 1H),7.92 (dd, J=9.1, 2.4 Hz, 1H), 6.96 (d, J=9.1 Hz, 1H), 4.62 (s, 1H), 4.43(s, 2H), 3.80-3.65 (m, 6H), 3.70-3.48 (m, 5H), 3.31-3.23 (m, 1H),2.18-2.11 (m, 1H), 1.98-1.91 (m, 1H), 1.82-1.64 (m, 2H).

Example 120:6-[4-[3-(3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of5-[3-[2-(benzyloxy)ethoxy]azetidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

To a solution of5-(3-hydroxyazetidin-1-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(300 mg, 0.82 mmol, 1.00 equiv) in DMF (20 mL), sodium hydride (20 mg,0.83 mmol, 2.00 equiv) was added in at 0° C., and then the resultingsolution was stirred for 5 min, and then [(bromoethoxy)methyl]benzene(331 mg, 1.65 mmol, 2.00 equiv) was dropped in, and then the resultingsolution was stirred for another 3 h at 0° C., and then the resultingsolution was quenched with 50 mL of H₂O, extracted with 3×50 mL of EtOAcand the organic layers combined, washed with 1×50 mL of brine andconcentrated under vacuum, and then the residue was applied onto asilica gel column eluting with EtOAc/petroleum ether (3:7) to afford 295mg (72%) of the title compound as light yellow oil. LCMS (ESI, m/z):500.21[M+H]⁺.

Step 2: Synthesis of5-[3-(2-hydroxyethoxy)azetidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

Under an atmosphere of hydrogen, a solution of5-[3-[2-(benzyloxy)ethyl]azetidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridin-3-one(265 mg, 0.55 mmol, 1.00 equiv) and Palladium carbon (13.5 mg, 0.05equiv) in methanol (20 mL) was stirred for 2 h at room temperature, andthen the solids were filtered out and the resulting solution wasconcentrated under vacuum to afford 221 mg (98%) of the title compoundas white oil. LCMS (ESI, m/z): 410.17M+H]⁺.

Step 3: Synthesis of Tert-Butyl3-[2-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]azetidin-3-yl]oxy)ethoxy]propanoate

To a solution of5-[3-(2-hydroxyethoxy)cyclobutyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(180 mg, 0.65 mmol, 1.00 equiv) in THF (6 mL), sodium hydride (21 mg,0.88 mmol, 2.00 equiv) was added in, the resulting solution was stirredfor 20 min at room temperature and then tert-butyl prop-2-enoate (112mg, 0.87 mmol, 2.00 equiv) was dropped in, and then the resultingsolution was stirred for 1 h at room temperature, and then the resultingsolution was quenched with of 15 mL of water, extracted with 15 mL ofEtOAc and the organic layers combined, washed with 1×15 mL of brine,dried over anhydrous sodium sulfate and concentrated under vacuum, andthen the residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1:3) to afford 80 mg (23%) of the title compoundas light brown oil. LCMS (ESI, m/z): 538.25[M+H]⁺.

Step 4: Synthesis of3-(2-(1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)azetidin-3-yloxy)ethoxy)propanoicAcid

A solution of tert-butyl3-[2-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]azetidin-3-yl]oxy)ethoxy]propanoate(180 mg, 0.34 mmol, 1.00 equiv) and TFA (2 mL) in DCM (10 mL) wasstirred for 40 min at room temperature, and then the resulting solutionwas concentrated under vacuum to afford 50 mg (28%) of the titlecompound as light yellow oil. LCMS (ESI, m/z): 352.11 [M+H]⁺.

Step 5: Synthesis of6-(4-[3-[2-([1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-3-yl]oxy)ethoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of3-[2-([1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-3-yl]oxy)ethoxy]propanoicacid (50 mg, 0.14 mmol, 1 equiv), DIEA (35.4 mg, 0.27 mmol, 2.00 equiv),HATU (52.0 mg, 0.14 mmol, 1.00 equiv) and Int-A4 (30.9 mg, 0.16 mmol,1.20 equiv) in DMF (20 mL) was stirred for 40 min at room temperature,and then the resulting solution was diluted with 20 ml of H2O, extractedwith 3×20 ml of EtOAc and the organic layer was combined, washed with1×20 ml of brine and concentrated under vacuum, and the residue waspurified by Prep-HPLC yielding the title compound (37.0 mg, 50.48%) as awhite solid. LCMS (ESI, m/z): 522.05 [M+H]+, ¹HNMR (CD3OD, 300 MHz) δ8.41 (d, J=1.8 Hz, 1H), 7.76 (dd, J 9.0, 2.4 Hz, 1H), 7.44 (s, 1H), 6.87(dd, J=9.0, 0.9 Hz, 1H), 4.57-4.40 (m, 3H), 4.21-4.17 (m, 2H), 3.90-3.73(m, 10H), 3.64 (s, 4H), 2.75 (t, J=6.1 Hz, 2H)

Example 121:6-(4-((1R,3R)-3-((1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-3-yl)methoxy)cyclobutanecarbonyl)piperazin-1-yl)nicotinonitrileand 6-(4-((1S,3S)-3-((1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-3-yl)methoxy)cyclobutanecarbonyl)piperazin-1-yl)nicotinonitrile

Step 1: Synthesis of (pyrrolidin-3-yl)methanol Hydrochloride

A solution of tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate(2.10 g, 10.44 mmol, 1.00 equiv) in hydrogen chloride/dioxane (10 mL)was stirred for 1 h at room temperature. The solvent was concentratedunder vacuum to afford 1.3 g crude of the title compound as a crudewhite solid. LCMS (ESI, m/z): 102.09 [M+H]+

Step 2: Synthesis of5-[3-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of (pyrrolidin-3-yl)methanol hydrochloride (900 mg, 6.54mmol, 1.00 equiv), Int-A6 (1.64 g, 4.99 mmol, 1.00 equiv), TEA (2 g,19.76 mmol, 5.00 equiv) in ethanol (20 mL) was stirred for 4 h at 80° C.The solvent was concentrated under vacuum and the residue was appliedonto a silica gel column eluting with EtOAc/petroleum ether (1:1) toafford 1.1 g (43%) of the title compound as a white solid. LCMS (ESI,m/z): 394.18 [M+H]+

Step 3: Synthesis of[1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-3-yl]methyl4-methylbenzene-1-sulfonate

A solution of5-[3-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(780 mg, 1.98 mmol, 1.00 equiv), 4-methylbenzene-1-sulfonyl chloride(570 mg, 2.99 mmol, 1.50 equiv), TEA (606 mg, 5.99 mmol, 3.00 equiv),4-dimethylaminopyridine (50 mg, 0.41 mmol, 0.20 equiv) in DCM (15 mL)was stirred for 8 h at room temperature. The solvent was concentratedunder vacuum and the residue was applied onto a silica gel columneluting with EtOAc/petroleum ether (1:1) to afford 500 mg (46%) of thetitle compound as a white solid. LCMS (ESI, m/z): 548.19 [M+H]+.

Step 4: Synthesis of methyl3-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-3-yl]methoxy)cyclobutane-1-carboxylate

A solution of[1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-3-yl]methyl4-methylbenzene-1-sulfonate (1.09 g, 1.99 mmol, 1.00 equiv), methyl3-hydroxycyclobutane-1-carboxylate (390 mg, 3.00 mmol, 1.50 equiv),sodium hydride (160 mg, 6.67 mmol, 2.00 equiv) in DMF (10 mL) wasstirred for 6 h at 80° C. The resulting solution was quenched with 60 mlH2O, then the solution was extracted with EtOAc (3×60 mL) and theorganic layers combined. The solution was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column eluting with EtOAc/petroleum ether (1:2) to afford 200mg (20%) of the title compound as a white solid. LCMS (ESI, m/z): 506.23[M+H]+

Step 5: Synthesis of3-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-3-yl]methoxy)cyclobutane-1-carboxylicAcid

A solution of methyl3-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-3-yl]methoxy)cyclobutane-1-carboxylate(200 mg, 0.40 mmol, 1.00 equiv), LiOH (48 mg, 2.00 mmol, 5.00 equiv),water (1 mL) in MeOH (5 ml) was stirred for 1 h at room temperature. ThepH value of the solution was adjusted to 5 with hydrogen chloride. Afterconcentration, the residue was applied onto a silica gel column elutingwith EtOAc/petroleum ether (2:1) to afford 130 mg (67%) of the titlecompound as a white solid. LCMS (ESI, m/z): 492.22 [M+H]+.

Step 6: Synthesis of6-(4-[3-[(2R)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2-phenylethoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrileand6-(4-[3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2-phenylethoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of3-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-3-yl]methoxy)cyclobutane-1-carboxylicacid (117 mg, 0.24 mmol, 1.00 equiv), HATU (117 mg, 0.31 mmol, 1.30equiv), DIEA (61.5 mg, 0.48 mmol, 2.00 equiv), Int-A4 (5 mL, 1.00 equiv)in DMF (2 mL) was stirred for 1 h at room temperature. The residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN toafford 100 mg (63%) of the title compound as a white solid. LCMS (ESI,m/z): 662.31 [M+H]+.

Step 7: Synthesis of6-(4-((1r,3r)-3-((1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-3-yl)methoxy)cyclobutanecarbonyl)piperazin-1-yl)nicotinonitrileand 6-(4-((is,3s)-3-((1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-3-yl)methoxy)cyclobutanecarbonyl)piperazin-1-yl)nicotinonitrile

A solution of6-[4-[3-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-3-yl]methoxy)cyclobutanecarbonyl]piperazin-1-yl]pyridine-3-carbonitrile(100 mg, 0.15 mmol, 1.00 equiv), TFA (1 mL) in DCM (5 mL) was stirredfor 1 h at room temperature. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN.Then the residue was further purified by Prep-HPLC yielding (afterarbitrary assignment of the stereochemistry) the title compounds,respectively, isomer A (12.9 mg, 16%) as a white solid. LCMS (ESI, m/z):532.30 [M+H]+, ¹H NMR (300 MHz, Methanol-d4) δ 8.44 (s, 1H), 7.92 (s,1H), 7.78 (dd, J=9.1, 2.4 Hz, 1H), 6.89 (dd, J=9.1, 0.8 Hz, 1H),4.01-3.97 (m, 1H), 3.80-3.69 (m, 9H), 3.68-3.60 (m, 2H), 3.59-3.40 (m,3H), 3.09-2.92 (m, 1H), 2.54 (q, J=8.4, 7.6 Hz, 3H), 2.23-2.02 (m, 3H),1.84-1.79 (m, 1H) and isomer B (4.1 mg, 5%) as a white solid. LCMS (ESI,m/z): 532.30 [M+H]+, ¹H NMR (300 MHz, Methanol-d4) δ 8.44 (s, 1H), 7.92(s, 1H), 7.78 (dd, J=9.1, 2.3 Hz, 1H), 6.89 (dd, J=9.1, 0.9 Hz, 1H),4.15-3.93 (m, 1H), 3.82-3.67 (m, 9H), 3.66-3.60 (m, 2H), 3.59-3.40 (m,2H), 3.39-3.31 (m, 2H), 2.55-2.50 (m, 3H), 2.26-2.11 (m, 3H), 1.92-1.75(m, 1H).

Example 122:6-[4-(3-[[(2S,4S)-4-methoxy-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of 1-tert-butyl 2-methyl(2S,4S)-4-methoxypyrrolidine-1,2-dicarboxylate

A solution of 1-tert-butyl 2-methyl(2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (5 g, 20.39 mmol, 1.00equiv), sodium hydride (1.63 g, 40.75 mmol, 2.00 equiv), iodomethane(5.7 g, 40.16 mmol, 2.00 equiv) in THF (50 mL) was stirred for 12 h atroom temperature. The reaction was quenched by the addition of 50 mLammonium chloride saturated aqueous solution. The resulting solution wasextracted with 3×70 mL of EtOAc and the organic layers combined andconcentrated under vacuum. Then the residue was applied onto a silicagel column eluting with EtOAc/petroleum ether (3/7) to afford 2.48 mg(47%) of the title compound as a yellow oil. LCMS (ESI, m/z):246.13[M+H]

Step 2: Synthesis of Tert-Butyl(2S,4S)-2-(hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate

A solution of(2S,4S)-1-[(tert-butoxy)carbonyl]-4-methoxypyrrolidine-2-carboxylic acid(1.1 g, 4.48 mmol, 1.00 equiv), B₂H₆/THF (10 mL) in THF (20 mL) wasstirred for 48h at room temperature. The resulting solution was dilutedwith 20 mL of water and extracted with 3×30 ml of EtOAc. The organiclayers combined and dried over Na₂SO₄. The resulting mixture wasconcentrated under vacuum to afford 1.1 g (crude) of the title compoundas a yellow oil. LCMS (ESI, m/z): 232.15[M+H]

Step 3: Synthesis of [(2S,4S)-4-methoxypyrrolidin-2-yl]methanolHydrochloride

A solution of tert-butyl(2S,4S)-2-(hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate (1.1 g,4.76 mmol, 1.00 equiv) in hydrogen chloride/dioxane (10 mL) was stirredfor 30 min at room temperature. The resulting mixture was concentratedunder vacuum to afford 818 mg of the title compound as yellow oil. LCMS(ESI, m/z): 132.09[M+H]

Step 4: Synthesis of5-[(2S,4S)-2-(hydroxymethyl)-4-methoxypyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of [(2S,4S)-4-methoxypyrrolidin-2-yl]methanol hydrochloride(818 mg, 4.88 mmol, 1.00 equiv), Int-A6 (805 mg, 2.45 mmol, 0.50 equiv),TEA (959 mg, 9.48 mmol, 2.00 equiv) in EtOH (10 mL) was stirred for 1 hat 80° C. The reaction mixture was concentrated under vacuum and theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1/1) to afford 460 mg (18%) of the title compoundas a white solid. LCMS (ESI, m/z): 424.18 [M+H]⁺

Step 5: Synthesis of methyl3-[[(2S,4S)-4-methoxy-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoate

A solution of5-[(2S,4S)-2-(hydroxymethyl)-4-methoxypyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(440 mg, 1.04 mmol, 1.00 equiv), sodium hydride (42 mg, 1.05 mmol, 1.00equiv), methyl prop-2-enoate (895 mg, 10.40 mmol, 10.00 equiv) in THF(10 mL) was stirred for 12 h at room temperature. Then the reaction wasquenched by the addition of water. The resulting solution was extractedwith 3×30 mL of EtOAc and the organic layers combined and concentratedunder vacuum. The residue was applied onto a silica gel column elutingwith EtOAc/petroleum ether (4/6) to afford 80 mg (15%) of the titlecompound as a yellow oil. LCMS (ESI, m/z): 510.22 [M+H]⁺

Step 6: Synthesis of3-[[(2S,4S)-4-methoxy-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicacid

A solution of methyl3-[[(2S,4S)-4-methoxy-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoate(80 mg, 0.16 mmol, 1.00 equiv), LiOH.H₂O (33 mg, 0.79 mmol, 5.00 equiv)in methanol (3 mL) and water (1 mL) was stirred for 2 h at roomtemperature. The pH value of the solution was adjusted to 6 withhydrogen chloride (1 M) and the solids were collected by filtration toafford 70 mg (90%) of the title compound as a white solid. LCMS (ESI,m/z): 496.20 [M+H]⁺

Step 7: Synthesis of6-[4-(3-[[(2S,4S)-4-methoxy-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-[[(2S,4S)-4-methoxy-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicacid (70 mg, 0.14 mmol, 1.00 equiv), HATU (80.6 mg, 0.21 mmol, 1.50equiv), DIEA (54.7 mg, 0.42 mmol, 3.00 equiv), Int-A4 (31.7 mg, 0.14mmol, 1.00 equiv) in DMF (3 mL) was stirred for 1 h at room temperature.The residue was purified by C18 reverse phase chromatography elutingwith H₂O/CH₃CN to afford 45 mg (48%) of the title compound as a yellowsolid. LCMS (ESI, m/z): 666.30 [M+H]⁺

Step 8: Synthesis of6-[4-(3-[[(2S,4S)-4-methoxy-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-(3-[[(2S,4S)-4-methoxy-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile(40 mg, 0.06 mmol, 1.00 equiv) in DCM (3 mL) and TFA (0.3 mL) wasstirred for 1 h at room temperature. After concentration, the residuewas purified by C18 reverse phase chromatography eluting with H₂O/CH₃CN.Then the residue was further purified by Prep-HPLC yielding the titlecompound (15.6 mg, 48%) as a white solid. LCMS (ESI, m/z): 536.52[M+H]+, 1H NMR (400 MHz, DMSO-d6) δ: 12.40 (s, 1H), 8.51 (d, J=2.3 Hz,1H), 8.01 (s, 1H), 7.89 (dd, J=9.1, 2.4 Hz, 1H), 6.93 (d, J=9.1 Hz, 1H),4.60 (s, 1H), 3.90 (p, J=7.3 Hz, 1H), 3.90-3.63 (m, 6H), 3.61-3.51 (m,5H), 3.51-3.43 (m, 3H), 3.47-3.34 (m, 3H), 2.55 (d, J=6.2 Hz, 2H), 2.31(dt, J=12.4, 7.4 Hz, 1H), 1.62 (dt, J=12.5, 7.5 Hz, 1H).

Example 123:6-[4-[(3R)-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(3S)-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of methyl 3-(methanesulfonyloxy)butanoate

A solution of methyl 3-hydroxybutanoate (980 mg, 8.30 mmol, 1.00 equiv),TEA (1.68 g, 16.60 mmol, 2.00 equiv), methanesulfonyl methanesulfonate(2.17 g, 12.46 mmol, 1.50 equiv) in DCM (10 mL) was stirred for 2 h atroom temperature. The resulting solution was extracted with 3×30 mL ofDCM and the organic layers combined, then the resulting mixture waswashed with 3×20 mL of ammonium chloride saturated aqueous solution anddried over Na₂SO₄. The reaction mixture was concentrated under vacuum toafford 1.51 g (93%) of the title compound as yellow oil. LCMS (ESI,m/z): 197.04 [M+H]⁺

Step 2: Synthesis of3-[[(2S)-1-[(tert-butoxy)carbonyl]pyrrolidin-2-yl]methoxy]butanoic Acid

A solution of methyl 3-(methanesulfonyloxy)butanoate (1.51 g, 7.70 mmol,1.00 equiv), sodium hydride (616 mg, 15.40 mmol, 2.00 equiv), tert-butyl(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.54 g, 7.65 mmol, 1.00equiv) in THF (15 mL) was stirred for 12 h at room temperature. Thereaction was quenched by the addition of 20 mL of water. The resultingsolution was extracted with 4×30 mL of EtOAc and the water layerscombined. The pH value of the water layers was adjusted to 6 withhydrogen chloride (1 M). The resulting solution was extracted with 5×20mL of DCM and the organic layers combined and concentrated under vacuumto afford 220 mg (9%) of the title compound as yellow oil. LCMS (ESI,m/z): 288.17 [M+H]⁺

Step 3: Synthesis of methyl 3-[[(2S)-pyrrolidin-2-yl]methoxy]butanoateHydrochloride

A solution of3-[[(2S)-1-[(tert-butoxy)carbonyl]pyrrolidin-2-yl]methoxy]butanoic acid(220 mg, 0.73 mmol, 1.00 equiv) in hydrogen chloride/dioxane (10 mL) wasstirred for 30 min at room temperature. The resulting mixture wasconcentrated under vacuum to afford 200 mg (crude) of the title compoundas yellow oil. LCMS (ESI, m/z): 188.17 [M+H]⁺

Step 4: Synthesis of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoicAcid

A solution of 3-[[(2S)-pyrrolidin-2-yl]methoxy]butanoic acidhydrochloride (200 mg, 0.89 mmol, 1.00 equiv), Int-A6 (147 mg, 0.45mmol, 0.50 equiv), TEA (181 mg, 1.79 mmol, 2.00 equiv) in EtOH (10 mL)was stirred for 2 h at 80° C. The reaction mixture was concentratedunder vacuum and the residue was applied onto a silica gel columneluting with DCM/methanol (9/1) to afford 190 mg (44%) of the titlecompound as yellow oil. LCMS (ESI, m/z): 480.21 [M+H]⁺

Step 5: Synthesis of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoicAcid

A solution of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoicacid in DCM (3 mL) and TFA (0.3 mL) was stirred for 1 h at roomtemperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN to afford 45 mg(88%) of the title compound as a white solid. LCMS (ESI, m/z): 350.12[M+H]⁺

Step 6: Synthesis of6-[4-[(3R)-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(3S)-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoicacid (45 mg, 0.13 mmol, 1.00 equiv), HATU (73.5 mg, 0.19 mmol, 1.50equiv), DIEA (50 mg, 0.39 mmol, 3.00 equiv), Int-A4 (28.8 mg, 0.13 mmol,1.00 equiv) in DMF (3 mL) was stirred for 1 h at room temperature. Theresulting solution was purified by C18 reverse phase chromatographyeluting with H₂O/CH₃CN. Then the residue was further purified byPrep-HPLC yielding (after arbitrary assignment of the stereochemistry)the title compounds, respectively, isomer A (14.4 mg, 22%) as a whitesolid. LCMS (ESI, m/z): 520.52 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ:12.34 (s, 1H), 8.51 (d, J=2.4 Hz, 1H), 8.01 (s, 1H), 7.93-7.82 (m, 1H),6.93 (d, J=9.1 Hz, 1H), 4.47 (m, 1H), 3.82 (q, J=6.1 Hz, 1H), 3.69-3.51(m, 10H), 3.59-3.48 (m, 1H), 3.21-3.16 (m, 1H), 2.59 (dd, J=15.5, 6.7Hz, 1H), 2.29 (dd, J=15.5, 5.7 Hz, 1H), 2.07 (m, 1H), 1.87 (s, 1H), 1.64(m, 2H), 1.09 (d, J=6.1 Hz, 3H) and isomer B (9 mg, 13%) as a whitesolid. LCMS (ESI, m/z): 520.55[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ: 12.34(s, 1H), 8.51 (d, J=2.4 Hz, 1H), 8.01 (s, 1H), 7.93-7.82 (m, 1H), 6.93(d, J=9.1 Hz, 1H), 4.47 (m, 1H), 3.82 (q, J=6.1 Hz, 1H), 3.69-3.51 (m,10H), 3.59-3.48 (m, 1H), 3.21-3.16 (m, 1H), 2.59 (dd, J=15.5, 6.7 Hz,1H), 2.29 (dd, J=15.5, 5.7 Hz, 1H), 2.07 (m, 1H), 1.87 (s, 1H), 1.64 (m,2H), 1.09 (d, J=6.1 Hz, 3H).

Example 124:6-(4-[2-[2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]methoxy)ethoxy]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1: Synthesis of6-[4-(2-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]acetyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of 2-[(tert-butyldimethylsilyl)oxy]ethan-1-ol (1111 mg, 6.30mmol, 1 equiv) in DMF (10 mL) was added NaH (302.4 mg, 12.60 mmol, 2equiv) in several batches at 0 degrees. The resulting solution wasstirred for 15 min at 0° C. Then6-[4-(2-chloroacetyl)piperazin-1-yl]pyridine-3-carbonitrile (2001 mg,7.56 mmol, 1.2 equiv) was added. The resulting solution was stirred foran additional 4 h at room temperature. The reaction was then quenched bythe addition of 10 mL of water. The resulting solution was extractedwith 3×30 mL of EtOAc and the organic layers combined. The resultingsolution was washed with 3×30 mL of NaCl (aq) and the organic layerscombined and concentrated under vacuum. The residue was applied onto asilica gel column eluting with EtOAc/petroleum ether (95/5) to afford751 mg (29.5%) of the title compound as colorless oil. LCMS (ESI, m/z):405.22 [M+H]⁺

Step 2: Synthesis of6-[4-[2-(2-hydroxyethoxy)acetyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-(2-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]acetyl)piperazin-1-yl]pyridine-3-carbonitrile(650 mg, 1.61 mmol, 1 equiv), TBAF (504.1 mg, 1.93 mmol, 1.2 equiv) inTHF (10 mL) was stirred for 2 h at room temperature. The reaction wasthen quenched by the addition of 10 mL of water. The resulting solutionwas extracted with 3×30 ml of DCM and the organic layers combined andconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with DCM/methanol (95/5) to afford 222 mg (47.6%) of thetitle compound as a white solid. LCMS (ESI, m/z): 291.14 [M+H]⁺

Step 3: Synthesis of6-(4-[2-[2-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]methoxy)ethoxy]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-[4-[2-(2-hydroxyethoxy)acetyl]piperazin-1-yl]pyridine-3-carbonitrile(100.6 mg, 0.35 mmol, 1.2 equiv) in THF (5 mL) was added NaH (13.9 mg,0.58 mmol, 2 equiv) at 0° C. The resulting solution was stirred for 15min at 0° C. Then[2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]methylmethanesulfonate (150 mg, 0.29 mmol, 1 equiv) was added. The resultingsolution was stirred for an additional 2 h at room temperature. Thereaction was then quenched by the addition of 10 mL of water. Theresulting solution was extracted with 3×30 mL of EtOAc and the organiclayers combined and dried over anhydrous sodium sulfate. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column eluting with DCM/methanol (99/1) to afford 33 mg (16%)of the title compound as yellow oil. LCMS (ESI, m/z): 714.30 [M+H]⁺

Step 4: Synthesis of6-(4-[2-[2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]methoxy)ethoxy]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-(4-[2-[2-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]methoxy)ethoxy]acetyl]piperazin-1-yl)pyridine-3-carbonitrile(33 mg, 0.05 mmol, 1 equiv) in DCM (5 mL) and TFA (0.5 mL) was stirredfor 2 h at room temperature. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN.Then the residue was further purified by Prep-HPLC yielding the titlecompound (5.1 mg, 18.9%) as a white solid. LCMS (ESI, m/z): 584.22[M+H]⁺, ¹H NMR (300 MHz, DMSO-d6) δ: 12.49 (s, 1H), 8.47 (d, J=2.3 Hz,1H), 8.01 (s, 1H), 7.85 (dd, J=9.1, 2.4 Hz, 1H), 7.27 (q, J=4.7 Hz, 3H),6.85 (d, J=9.1 Hz, 1H), 4.99 (s, 2H), 4.93 (s, 2H), 4.53 (s, 2H), 4.19(s, 2H), 3.61 (d, J=4.2 Hz, 8H), 3.49 (m, 4H).

Example 125:6-[4-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]azetidine-1-carbonyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of 4-nitrophenyl4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate

A solution of Int-A4 (1 g, 5.31 mmol, 1 equiv), DIEA (1.38 g, 10.68mmol, 2.01 equiv), 4-nitrophenyl carbonochloridate (1.07 g, 5.31 mmol,1.00 equiv) in DCM (20 mL) was stirred for 2 h at room temperature. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column eluting with EtOAc/petroleum ether (70/30) toafford 1.7 g (90%) of the title compound as a yellow solid. LCMS (ESI,m/z): 354.33 [M+H]⁺

Step 2: Synthesis of6-[4-(3-hydroxyazetidine-1-carbonyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of 4-nitrophenyl4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate (1.7 g, 4.81 mmol, 1equiv), DIEA (1.25 g, 9.67 mmol, 2.01 equiv), azetidin-3-olhydrochloride (1.05 g, 9.58 mmol, 1.99 equiv) in butan-1-ol (20 mL) wasstirred for 16 h at 120° C. The resulting mixture was concentrated undervacuum. The residue was dissolved in 30 mL of DCM. The organic layer waswashed with 20 ml of saturated sodium carbonate aqueous. The organiclayers combined and dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was applied onto a silica gel column elutingwith DCM/methanol (5/95) to afford 600 mg (43%) of the title compound asa white solid. LCMS (ESI, m/z): 288.32 [M+H]⁺

Step 3: Synthesis of Tert-Butyl(2S)-2-[([1-[4-(5-cyanopyridin-2-yl)piperazine-1-carbonyl]azetidin-3-yl]oxy)methyl]pyrrolidine-1-carboxylate

A solution of6-[4-(3-hydroxyazetidine-1-carbonyl)piperazin-1-yl]pyridine-3-carbonitrile(600 mg, 2.09 mmol, 1.00 equiv), NaH (250 mg, 10.42 mmol, 4.99 equiv),tert-butyl (2S)-2-[(methanesulfonyloxy)methyl]pyrrolidine-1-carboxylate(583 mg, 2.09 mmol, 1 equiv) in THF (30 mL) was stirred for 3 days at80° C. The reaction was then quenched by the addition of 30 mL of water.The resulting solution was extracted with 3×30 mL of EtOAc and theorganic layers combined and dried over anhydrous sodium sulfate. Theorganic layer was concentrated under vacuum. The residue was appliedonto a silica gel column eluting with EtOAc/petroleum ether (90/10) toafford 250 mg (25%) of the title compound as yellow oil. LCMS (ESI,m/z): 471.56 [M+H]⁺

Step 4: Synthesis of6-[4-(3-[[(2S)-pyrrolidin-2-yl]methoxy]azetidine-1-carbonyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of tert-butyl(2S)-2-[([1-[4-(5-cyanopyridin-2-yl)piperazine-1-carbonyl]azetidin-3-yl]oxy)methyl]pyrrolidine-1-carboxylate(150 mg, 0.32 mmol, 1 equiv), TFA (0.3 mL) in DCM (5 mL) was stirred for2 h at room temperature. The resulting mixture was concentrated undervacuum to afford 130 mg (crude) of the title compound as yellow oil.LCMS (ESI, m/z): 371.45 [M+H]⁺

Step 5: Synthesis of6-[4-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]azetidine-1-carbonyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-(3-[[(2S)-pyrrolidin-2-yl]methoxy]azetidine-1-carbonyl)piperazin-1-yl]pyridine-3-carbonitrile(120 mg, 0.32 mmol, 1 equiv), TEA (98 mg, 0.97 mmol, 2.99 equiv), Int-A6(127.3 mg, 0.39 mmol, 1.20 equiv) in EtOH (20 mL) was stirred for 16 hat 70° C. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column eluting with EtOAc toafford 120 mg (56%) of the title compound as yellow oil. LCMS (ESI,m/z): 663.78 [M+H]⁺

Step 6: Synthesis of6-[4-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]azetidine-1-carbonyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]azetidine-1-carbonyl)piperazin-1-yl]pyridine-3-carbonitrile(120 mg, 0.18 mmol, 1 equiv), TFA (0.8 mL) in DCM (8 mL) was stirred for1 h at room temperature. After concentration, the residue was purifiedby C18 reverse phase chromatography eluting with H₂O/CH₃CN. Then theresidue was further purified by Prep-HPLC yielding the title compound(35.0 mg, 36.3%) as a white solid. LCMS (ESI, m/z): 532.52 [M+H]⁺, 1HNMR(300 MHz, DMSO-d₆) δ: 12.36 (s, 1H), 8.50 (d, J=2.2 Hz, 1H), 8.06 (s,1H), 7.92-7.82 (m, 1H), 6.91 (d, J=9.2 Hz, 1H), 4.58 (s, 1H), 4.25 (s,1H), 4.05 (d, J=8.2 Hz, 2H), 3.64-3.44 (m, 10H), 3.32-3.15 (m, 4H),2.36-2.11 (m, 1H), 1.91 (s, 1H), 1.67 (m, 2H).

Example 126:4-(5-cyanopyridin-2-yl)-N-(2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]ethyl)piperazine-1-carboxamide

Step 1: Synthesis of5-[(2S)-2-[(2-hydroxyethoxy)methyl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methylmethanesulfonate (900 mg, 1.91 mmol, 1.00 equiv), and Cs₂CO₃ (1.868 g,5.73 mmol, 3.00 equiv) in ethane-1,2-diol (20 mL) was stirred for 6 h at80° C. The reaction was quenched by the addition 150 ml of water andextracted with 300 mL of EtOAc, the organic layers combined andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with EtOAc/petroleum ether (1/1) to afford 400 mg (48%) of thetitle compound as yellow oil. LCMS (ESI, m/z): 438.53 [M+H]⁺

Step 2: Synthesis of5-[(2S)-2-[(2-azidoethoxy)methyl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[(2S)-2-[(2-hydroxyethoxy)methyl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(400 mg, 0.91 mmol, 1.00 equiv), DBU (278 mg, 1.83 mmol, 3.00 equiv),and DPPA (502 mg, 1.82 mmol, 2.00 equiv) in toluene (5 mL) was stirredfor 5 h at 80° C. After added EtOAc 300 mL to the resulting solution,the resulting mixture was washed with 2×100 mL of sodium carbonate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with EtOAc/petroleum ether (3/7) to afford 320 mg (76%) of thetitle compound as yellow oil. LCMS (ESI, m/z): 463.54 [M+H]⁺

Step 3: Synthesis of5-[(2S)-2-[(2-aminoethoxy)methyl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[(2S)-2-[(2-azidoethoxy)methyl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(320 mg, 0.69 mmol, 1.00 equiv), and Palladium carbon (80 mg) inmethanol (20 mL) was stirred 5 h at 60° C. under the atmosphere ofHydrogen. The solids were filtered out. The resulting mixture wasconcentrated under vacuum to afford 260 mg (86%) of the title compoundas green solids. LCMS (ESI, m/z): 437.54 [M+H]⁺

Step 4: Synthesis of 4-nitrophenyl4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate

A solution of Int-A4 (1 g, 3.83 mmol, 1.00 equiv), TEA (1.36 g, 13.44mmol, 3.50 equiv), and 4-nitrophenyl carbonochloridate (773 mg, 3.84mmol, 1.00 equiv) in DCM (50 mL) was stirred 1 h at 25° C. Then added 5mL EA. The solids were collected by filtration to afford 1 g (74%) ofthe title compound as light yellow solids. LCMS (ESI, m/z): 354.33[M+H]⁺.

Step 5: Synthesis of4-(5-cyanopyridin-2-yl)-N-(2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]ethyl)piperazine-1-carboxamide

A solution of5-[(2S)-2-[(2-aminoethoxy)methyl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(250 mg, 0.57 mmol, 1.00 equiv), potassium carbonate (237 mg, 1.71 mmol,3.00 equiv), and 4-nitrophenyl4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate (364 mg, 1.03 mmol, 1.80equiv) in DMF (4 mL) was stirred 5 h at 80° C. The reaction mixture wasdiluted with H₂O (200 mL). The resulting solution was extracted withEtOAc 3×150 mL, then the organic layers was combined and concentratedunder vacuum. The residue was applied onto a silica gel column withEtOAc to afford 322 mg (86%) of the title compound as colorless oil.LCMS (ESI, m/z): 651.77 [M+H]⁺

Step 6: Synthesis of4-(5-cyanopyridin-2-yl)-N-(2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]ethyl)piperazine-1-carboxamide

A solution of4-(5-cyanopyridin-2-yl)-N-(2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]ethyl)piperazine-1-carboxamide(300 mg, 0.46 mmol, 1.00 equiv), and TFA/DCM (12 mL) in DCM (10 mL) wasstirred 1 h at 25° C. The pH value of the solution was adjusted to 8with NH3/CH3OH. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN yielding the titlecompound 88.2 mg (37%) as a white solid. LCMS (ESI, m/z): 521.2 [M+H]⁺,¹H NMR (400 MHz, Methanol-d₄) δ 8.43-8.42 (d, J=1.6, 1H), 8.18 (s, 1H),7.79-7.75 (m, 1H), 7.21-6.86 (m, 1H), 4.62-4.59 (d, 1H), 3.79-3.71 (m,4H), 3.66-3.64 (m, 2H), 3.60-3.42 (m, 8H), 3.43-3.26 (m, 2H), 2.26-2.23(t, J=6.4 Hz, 1H), 2.01-1.99 (t, J=5.4 Hz, 1H), 1.74-1.70 (m, 2H).

Example 127:4-(5-cyanopyridin-2-yl)-N-(2-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]ethyl)piperazine-1-carboxamide

Step 1: Synthesis of4-bromo-5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of Int-A8 (5.6 g, 14.58 mmol, 1.00 equiv), TEA (2.95 g, 29.15mmol, 2.00 equiv), and [(2S)-pyrrolidin-2-yl]methanol (1.47 g, 14.53mmol, 1.00 equiv) in ethanol (200 mL) was stirred for 1 h at 80° C. Theresulting solution was extracted with EtOAc 3×50 mL. Then the organiclayers was combined and concentrated under vacuum to afford 5 g (85%) ofthe title compound as yellow solids. LCMS (ESI, m/z): 405.37 [M+H]⁺

Step 2: Synthesis of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-3-oxo-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazine-4-carbonitrile

A solution of4-bromo-5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(2 g, 4.95 mmol, 1.00 equiv), and CuCN (1.3 g, 3.00 equiv) in NMP (10mL) was stirred for 2 h at 120° C. The resulting solution was extractedwith 3×30 mL of ether and the organic layers combined. The residue wasapplied onto a silica gel column with EtOAc/petroleum ether (I/O) toafford 680 mg (39%) of the title compound as white solids. LCMS (ESI,m/z): 351.49 [M+H]⁺

Step 3: Synthesis of3-[[2-(5-cyano-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)-2,3-dihydro-1H-isoindol-1-yl]methoxy]propanoate

A solution of5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-3-oxo-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazine-4-carbonitrile(360 mg, 0.90 mmol, 1.00 equiv), Cs₂CO₃ (368 mg, 1.13 mmol, 1.10 equiv),and tert-butyl prop-2-enoate (659 mg, 5.14 mmol, 5.00 equiv) in CH₃CN(20 mL) was stirred 2 days at 40° C. The residue was applied onto asilica gel column with EtOAc/petroleum ether (1/2) to afford 130 mg(27%) of the title compound as white solids. LCMS (ESI, m/z): 479.66[M+H]⁺

Step 4: Synthesis of3-[[(2S)-1-(5-cyano-6-oxo-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy]propanoicAcid

A solution of tert-butyl3-[[(2S)-1-(5-cyano-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy]propanoate(130 mg, 0.27 mmol, 1.00 equiv), in hydrogen chloride/dioxane (20 mL)was stirred for 1 h at 25° C. The crude product was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN (1/1) to afford 70mg (88%) of the title compound as white solids. LCMS (ESI, m/z): 293.29[M+H]⁺.

Step 5: Synthesis of5-[(2S)-2-([3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-3-oxopropoxy]methyl)pyrrolidin-1-yl]-3-oxo-2,3-dihydropyridazine-4-carbonitrile

A solution of3-[[(2S)-1-(5-cyano-6-oxo-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy]propanoicacid (60 mg, 0.21 mmol, 1.00 equiv), HATU (80 mg, 0.21 mmol, 1.00equiv), DIEA (108 mg, 0.84 mmol, 4.00 equiv), and Int-A4 (55 mg, 0.21mmol, 1.00 equiv) in DMF (2 mL) was stirred for 1 h at 25° C. The crudeproduct was purified by C18 reverse phase chromatography eluting withH₂O/CH3CN yielding the title compound 18.7 mg (20%) as white solids.LCMS (ESI, m/z): 463.19 [M+H]⁺, ¹H NMR (Methanol-d₄, 400 MHz) δ: 8.42(dd, J=2.4, 0.8 Hz, 1H), 7.89 (s, 1H), 7.76 (dd, J=9.1, 2.4 Hz, 1H),6.86 (dd, J=9.1, 0.8 Hz, 1H), 4.70 (dr, 1H), 4.03 (dr, 1H), 3.78-3.58(dd, J=6.3, 4.9 Hz, 13H), 2.67-2.63 (t, J=5.8 Hz, 2H), 2.17-1.95 (m,4H).

Example 128:6-[4-[(3R)-methyl-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(3S)-methyl-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoyl]-piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of methyl (2E)-4-bromo-3-methylbut-2-enoate

A solution of methyl 3-methylbut-2-enoate (5 g, 43.80 mmol, 1.00 equiv),NBS (8.5 g, 47.76 mmol, 1.09 equiv) and BPO (1.1 g, 4.29 mmol, 0.10equiv) in CCl₄ (200 mL) was stirred overnight at 80° C. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column with EtOAc/petroleum ether (1:10). This resulted in 6g (71%) of the title compound as an oil. GCMS (m/z): 190.

Step 2: Synthesis of(2E)-3-methyl-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-2-enoate

A solution of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1.6 g, 4.07 mmol, 1.00 equiv), methyl (2E)-4-bromo-3-methylbut-2-enoate(870 mg, 4.51 mmol, 1.11 equiv), Rockphos (574 mg), Cs₂CO₃ (2.7 g, 8.29mmol, 2.04 equiv) and Pd₂(dba)₃-CHCl₃ (870 mg) in dioxane (30 mL) wasstirred for 20 h at 100° C. under an inert atmosphere of nitrogen. Theresulting solution was diluted with 200 mL of EtOAc. The resultingmixture was washed with 2×50 mL of water and 1×50 mL of Brine. Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was applied onto a silica gel column withEtOAc/petroleum ether (1:2). This resulted in 1.3 g (crude) of the titlecompound as oil. LCMS (ESI, m/z): 506.23 [M+H]⁺

Step 3: Synthesis of3-methyl-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoate

A solution of methyl(2E)-3-methyl-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-2-enoate(1.3 g, 2.57 mmol, 1.00 equiv) and palladium carbon (200 mg) in DCM (30mL) and methanol (30 mL) was stirred for 2 h at room temperature underan inert atmosphere of hydrogen. The solids were filtered out. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with EtOAc/petroleum ether (1:2). This resultedin 1 g (crude) of the title compound as a solid. LCMS (ESI, m/z): 508.24[M+H]⁺.

Step 4: Synthesis of3-methyl-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoicAcid

To a stirred solution of methyl3-methyl-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoate(330 mg, 0.65 mmol, 1.00 equiv) in THF (6 mL) and water (2 mL), LiOH.H₂O(100 mg, 2.38 mmol, 3.67 equiv) was added. The resulting solution wasstirred for 5 h at room temperature. The pH value of the solution wasadjusted to 1 with hydrogen chloride (1 M M). The resulting solution wasdiluted with 200 mL of EtOAc. The resulting mixture was washed with 2×50mL of Brine. The organic layer was dried over anhydrous sodium sulfateand concentrated under vacuum. This resulted in 300 mg (crude) of thetitle compound as an oil. LCMS (ESI, m/z): 494.23 [M+H]⁺.

Step 5: Synthesis of3-methyl-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoicAcid

A solution of3-methyl-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoicacid (300 mg, 0.61 mmol, 1.00 equiv) in hydrogen chloride/dioxane (10mL) was stirred overnight at room temperature. The resulting mixture wasconcentrated under vacuum. This resulted in 200 mg (crude) of the titlecompound as a solid. LCMS (ESI, m/z): 364.15 [M+H]⁺.

Step 6: Synthesis of6-[4-[(3R)-methyl-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(3S)-methyl-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrile

To a stirred solution of3-methyl-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoicacid (200 mg, 0.55 mmol, 1.00 equiv) in DMF (10 mL), Int-A4 (125 mg,0.66 mmol, 1.21 equiv), DIPEA (0.5 mL) and HATU (280 mg, 0.74 mmol, 1.34equiv) was added. The resulting solution was stirred for 2 h at roomtemperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN. Then the residuewas further purified by Prep-HPLC and Chiral-Prep-HPLC yielding (afterarbitrary assignment of the stereochemistry) the title compounds,respectively, isomer A (47.7 mg, 73%) as a white solid. LCMS (ESI, m/z):534.35 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 8.45 (dd, J=2.3, 0.8 Hz,1H), 8.22 (s, 1H), 7.78 (dd, J=9.1, 2.4 Hz, 1H), 6.90 (dd, J=9.1, 0.8Hz, 1H), 4.73-4.63 (m, 1H), 3.78-3.62 (m, 8H), 3.59-3.53 (m, 2H),3.43-3.35 (m, 4H), 2.45 (q, J=8.8 Hz, 1H), 2.29-2.13 (m, 3H), 2.07-1.97(m, 1H), 1.83-1.61 (m, 2H), 0.95 (d, J=6.4 Hz, 3H). Rt=4.919 min(CHIRALPAK IG-3, 0.46*10 cm; 3 um, MtBE (0.1% DEA):MeOH=90:10, 1.0ml/min) and isomer B (41.3 mg, 64%) as a white solid. LCMS (ESI, m/z):534.15 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 8.45 (dd, J=2.3, 0.8 Hz,1H), 8.20 (s, 1H), 7.78 (dd, J=9.1, 2.3 Hz, 1H), 6.89 (dd, J=9.1, 0.8Hz, 1H), 4.68 (qd, J=7.9, 2.7 Hz, 1H), 3.79-3.65 (m, 8H), 3.64-3.57 (m,2H), 3.46 (dd, J=9.1, 4.2 Hz, 1H), 3.43-3.34 (m, 2H), 3.25 (dd, J=9.2,6.0 Hz, 1H), 2.47 (q, J=9.0 Hz, 1H), 2.29-2.14 (m, 3H), 2.06-1.98 (m,1H), 1.83-1.62 (m, 2H), 0.90 (d, J=6.3 Hz, 3H). Rt=6.472 min (CHIRALPAKIG-3, 0.46*10 cm; 3 um, MtBE (0.1% DEA):MeOH=90:10, 1.0 ml/min).

Example 129:6-[4-[(3R)-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrrolidine-1-carbonyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(3S)-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrrolidine-1-carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of 4-nitrophenyl4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate

A solution of Int-A4 (500 mg, 2.23 mmol, 1.00 equiv) and TEA (676 mg,6.68 mmol, 3.00 equiv) in DCM (10 mL), then 4-nitrophenylcarbonochloridate (450 mg, 2.23 mmol, 1.00 equiv) was added in, then theresulting solution was stirred for 1 h at room temperature, and then theresulting solution was diluted with 10 mL of Water, extracted with 2×10mL of DCM and the organic layers were combined, washed with 1×10 mL ofbrine, dried over anhydrous sodium sulfate and concentrated undervacuum, and then the residue was applied onto a silica gel columneluting with EtOAc/petroleum ether to afford 520 mg (66%) of the titlecompound as a yellow solid. LCMS (ESI, m/z): 354.11 [M+H]⁺.

Step 2: Synthesis of6-[4-(3-hydroxypyrrolidine-1-carbonyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of pyrrolidin-3-ol hydrochloride (175 mg, 1.42 mmol, 1.00equiv), 4-nitrophenyl 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate(500 mg, 1.42 mmol, 1.00 equiv) and potassium carbonate (390 mg, 2.82mmol, 2.00 equiv) in DMF (5 mL) was stirred for 2 h at 80° C., and thenthe resulting solution was diluted with 15 mL of water, extracted with3×15 mL of EtOAc and the organic layers were combined, washed with 1×15mL of brine, dried over anhydrous sodium sulfate and concentrated undervacuum, and then the residue was applied onto a silica gel columneluting with EtOAc/petroleum ether to afford 280 mg (66%) of the titlecompound as a yellow solid. LCMS (ESI, m/z): 302.15 [M+H]⁺.

Step 3: Synthesis of Tert-Butyl(2S)-2-[([1-[4-(5-cyanopyridin-2-yl)piperazine-1-carbonyl]pyrrolidin-3-yl]oxy)methyl]pyrrolidine-1-carboxylate

A solution of6-[4-(3-hydroxypyrrolidine-1-carbonyl)piperazin-1-yl]pyridine-3-carbonitrile(400 mg, 1.33 mmol, 1.00 equiv) in DMF (8 mL), and then sodium hydride(159 mg, 6.62 mmol, 3.00 equiv) was added in, then the resultingsolution was stirred for 15 min at room temperature, and then tert-butyl(2S)-2-[(methanesulfonyloxy)methyl]pyrrolidine-1-carboxylate (556 mg,1.99 mmol, 1.50 equiv) was added in, the resulting solution was stirredfor 12 h at 80° C. in an oil bath, then the resulting solution wasquenched by the addition of 15 mL of water, extracted with 3×15 mL ofEtOAc and the organic layers were combined, washed with 1×15 mL of brineand dried over anhydrous sodium sulfate and concentrated under vacuum,and then the residue was applied onto a silica gel column eluting withEtOAc to afford 85 mg (13%) of the title compound as a light yellowsolid. LCMS (ESI, m/z): 485.28 [M+H]⁺

Step 4: Synthesis of6-[4-(3-[[(2S)-pyrrolidin-2-yl]methoxy]pyrrolidine-1-carbonyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of tert-butyl(2S)-2-[([1-[4-(5-cyanopyridin-2-yl)piperazine-1-carbonyl]pyrrolidin-3-yl]oxy)methyl]pyrrolidine-1-carboxylate(85 mg, 0.18 mmol, 1.00 equiv) and TFA (0.2 mL) in DCM (1.0 mL) wasstirred for 1 h at room temperature, and then the resulting solution wasconcentrated under vacuum to afford 56 mg of the title compound as crudeyellow oil. LCMS (ESI, m/z): 385.23 [M+H]⁺.

Step 5: Synthesis of6-[4-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrrolidine-1-carbonyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of Int-A6 (47.7 mg, 0.15 mmol, 1.00 equiv),6-[4-(3-[[(2S)-pyrrolidin-2-yl]methoxy]pyrrolidine-1-carbonyl)piperazin-1-yl]pyridine-3-carbonitrile(50 mg, 0.13 mmol, 1.00 equiv) and TEA (51.7 mg, 0.51 mmol, 3.00 equiv)in ethanol (5 mL) was stirred for 1 h at 60° C., and then the resultingsolution was concentrated under vacuum, and then the residue was appliedonto a silica gel column eluting with DCM/methanol (15:1) to afford 89mg (91%) of the title compound as a light yellow solid. LCMS (ESI, m/z):677.31 [M+H]+.

Step 6: Synthesis of6-[4-[(3R)-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrrolidine-1-carbonyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(3S)-3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrrolidine-1-carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]pyrrolidine-1-carbonyl)piperazin-1-yl]pyridine-3-carbonitrile(85 mg, 0.13 mmol, 1 equiv) and TFA (1 mL) in DCM (5 mL) was stirred for2 h at room temperature, and then the resulting solution wasconcentrated under vacuum and then the residue was purified by Prep-HPLCyielding (after arbitrary assignment of the stereochemistry), the titlecompounds, respectively, isomer A (14.1 mg, 20.5%) as a white solid.LCMS (ESI, m/z): 547.15 [M+H]⁺, ¹HNMR (Methanol-d4, 300 MHz): δ 8.43 (d,J=2.3 Hz, 1H), 8.16 (s, 1H), 7.78 (dd, J=9.1, 2.4 Hz, 1H), 6.89 (d,J=9.6 Hz, 1H), 4.67-4.61 (m, 1H), 4.07 (s, 1H), 3.80-3.65 (m, 6H),3.57-3.35 (m, 7H), 3.33-3.26 (m, 3H), 2.27 (d, J=7.7 Hz, 1H), 2.03-1.82(m, 3H), 1.81-1.56 (m, 2H); tR=3.580 min (CHIRALPAK AS-3, 0.46*100 mm; 3um, EtOH (0.1% DEA), 4.0 mL/min) and isomer B (9.7 mg, 14.1%) as a whitesolid. LCMS (ESI, m/z): 547.15 [M+H]⁺, ¹HNMR (Methanol-d4, 300 MHz): δ8.43 (d, J=2.4, 1H), 8.15 (s, 1H), 7.78 (dd, J=9.1, 2.4 Hz, 1H), 6.90(d, J=9.0 Hz, 1H), 4.65-4.61 (m, 1H), 4.09 (s, 1H), 3.81-3.66 (m, 6H),3.57 (dd, J=12.0, 4.2 Hz, 1H), 3.47-3.34 (m, 6H), 3.31-3.24 (m, 3H),2.26 (dt, J=13.8, 6.7 Hz, 1H), 2.06-1.97 (m, 2H), 1.93-1.55 (m, 3H).tR=2.821 min (CHIRALPAK IA, 0.46*55 cm; 5 um, EtOH (0.1% DEA), 4.0mL/min).

Example 130:6-[4-[3-([1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]piperidin-2-yl]methoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of4-bromo-5-[2-(hydroxymethyl)piperidin-1-yl]-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of (piperidin-2-yl)methanol (2 g, 17.3 mmol, 1.00 equiv),DIEA (9 g, 69.6 mmol, 4.00 equiv), Int-A8 (6.6 g, 17.2 mmol, 1.00 equiv)in IPA (30 mL) was stirred for 12 h at 100° C. The solvent wasconcentrated under vacuum and the residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (1:2) to afford 4.17 g (58%)of the title compound as a solid. LCMS (ESI, m/z): 418.12 [M+H]+

Step 2: Synthesis of methyl3-[[1-(5-bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)piperidin-2-yl]methoxy]propanoate

A solution of4-bromo-5-[2-(hydroxymethyl)piperidin-1-yl]-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(830 mg, 2.00 mmol, 1.00 equiv), Cs₂CO₃ (1300 mg, 4 mmol, 2.00 equiv),methyl prop-2-enoate (720 mg, 8.00 mmol, 4.00 equiv) in DMF (15 mL) wasstirred for 16 h at room temperature. The resulting solution wasquenched with 60 ml H₂O, then the solution was extracted with EtOAc(3×60 mL) and the organic layers combined. The solution was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(20:80) to afford 800 mg (95%) of the title compound as a solid. LCMS(ESI, m/z): 504.16 [M+H]+

Step 3: Synthesis of methyl3-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]piperidin-2-yl]methoxy)propanoate

A solution of methyl3-[[1-(5-bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)piperidin-2-yl]methoxy]propanoate(750 mg, 1.49 mmol, 1.00 equiv), CuI (30 mg, 0.16 mmol, 0.10 equiv),ethyl 2,2-difluoro-2-sulfoacetate (1.5 g, 7.28 mmol, 5.00 equiv) in DMF(10 mL) was stirred for 5 h at 80° C. The resulting solution wasquenched with 30 ml H₂O, then the solution was extracted with EtOAc(3×30 mL) and the organic layers combined. The solution was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(30:70) to afford 750 mg (80%) of the title compound as a solid. LCMS(ESI, m/z): 494.23 [M+H]+.

Step 4: Synthesis of3-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]piperidin-2-yl]methoxy)propanoicacid

A solution of methyl3-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]piperidin-2-yl]methoxy)propanoate(750 mg, 1.52 mmol, 1.00 equiv), water (2 mL), LiOH (180 mg, 7.52 mmol,5.00 equiv) in THF (10 mL) was stirred for 2h at room temperature. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford 500 mg (66%) of thetitle compound as a solid. LCMS (ESI, m/z): 480.23 [M+H]+

Step 5: Synthesis of6-[4-[3-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]piperidin-2-yl]methoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]piperidin-2-yl]methoxy)propanoicacid (500 mg, 1.04 mmol, 1.00 equiv), HATU (520 mg, 1.37 mmol, 1.30equiv), DIEA (270 mg, 2.09 mmol, 2.00 equiv), Int-A4 (200 mg, 1.06 mmol,1.00 equiv) in DMF (3 mL) was stirred for 1 h at room temperature. Theresulting solution was quenched with of 20 ml H₂O, then the solution wasextracted with EtOAc (3×30 mL) and the organic layers combined. Thesolution was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1:1) to afford 550 mg (81%) of the title compoundas a solid LCMS (ESI, m/z): 650.31 [M+H]+

Step 6: Synthesis of6-[4-[3-([1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]piperidin-2-yl]methoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-[3-([1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]piperidin-2-yl]methoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile(550 mg, 0.85 mmol, 1.00 equiv), TFA (2 mL) in DCM (10 mL) was stirredfor 1 h at room temperature. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN.Then the residue was further purified by Prep-HPLC yielding the titlecompound (57.0 mg, 13.1%) as a white solid. LCMS (ESI, m/z): 520.30[M+H]+, ¹HNMR (DMSO-d6, 300 MHz) δ: 12.53 (s, 1H), 8.51 (d, J=1.8 Hz,1H), 7.92-7.87 (m, 2H), 6.93 (d, J=9.0 Hz, 1H), 3.96 (s, 1H), 3.79 (t,J=2.1 Hz, 1H), 3.66-3.42 (m, 12H), 3.24-3.20 (m, 1H), 2.49-2.43 (m, 2H),1.84-1.73 (m, 3H), 1.71-1.52 (m, 3H).

Example 131:6-(4-(3-((1-(5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)piperidin-2-yl)methoxy)propanoyl)piperazin-1-yl)nicotinonitrile

Step 1:3-((1-(5-bromo-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)piperidin-2-yl)methoxy)propanoicAcid

A solution of methyl3-((1-(5-bromo-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)piperidin-2-yl)methoxy)propanoate(503 mg, 1.00 mmol, 1.00 equiv), water (2 mL), LiOH (120 mg, 5.00 mmol,5.00 equiv) in THF (10 mL) was stirred for 2h at room temperature. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford 395 mg (81%) of thetitle compound as a solid. LCMS (ESI, m/z): 490.14 [M+H]+.

Step 2:6-(4-(3-((1-(5-bromo-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)piperidin-2-yl)methoxy)propanoyl)piperazin-1-yl)nicotinonitrile

A solution of3-((1-(5-bromo-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)piperidin-2-yl)methoxy)propanoicacid (395 mg, 0.80 mmol, 1.00 equiv), HATU (365 mg, 0.96 mmol, 1.20equiv), DIEA (230 mg, 1.60 mmol, 2.00 equiv), Int-A4 (150 mg, 0.80 mmol,1.00 equiv) in DMF (3 mL) was stirred for 1 h at room temperature. Theresulting solution was quenched with of 20 ml H₂O, then the solution wasextracted with EtOAc (3×30 mL) and the organic layers combined. Thesolution was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1:1) to afford 417 mg (79%) of the title compoundas a solid LCMS (ESI, m/z): 660.24 [M+H]+.

Step 3:6-(4-(3-((1-(5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)piperidin-2-yl)methoxy)propanoyl)piperazin-1-yl)nicotinonitrile

A solution of6-(4-(3-((1-(5-bromo-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)piperidin-2-yl)methoxy)propanoyl)piperazin-1-yl)nicotinonitrile(417 mg, 0.63 mmol, 1.00 equiv), TFA (2 mL) in DCM (10 mL) was stirredfor 1 h at room temperature. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN.Then the residue was further purified by Prep-HPLC yielding the titlecompound (32.5 mg, 30.1%) as a white solid. LCMS (ESI, m/z): 532.25[M+H]+, ¹HNMR (DMSO-d₆, 300 MHz) δ: 12.68 (s, 1H), 8.51 (d, J=1.8 Hz,1H), 7.89 (dd, J=9.0, 2.4 Hz, 1H), 7.68 (s, 1H), 6.93 (d, J=9.0 Hz, 1H),4.15 (s, 1H), 3.83 (t, J=2.1 Hz, 1H), 3.68-3.66 (m, 4H), 3.65-3.40 (m,8H), 3.26-3.20 (m, 1H), 2.49-2.43 (m, 2H), 1.84-1.52 (m, 6H).

Example 132:N-[3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-3-oxopropyl]-2-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]acetamide

Step 1: Synthesis of Tert-ButylN-[3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-3-oxopropyl]carbamate

A solution of Int-A4 (500 mg, 2.23 mmol, 1.00 equiv), DIEA (863 mg, 6.68mmol, 3.00 equiv), HATU (1.27 g, 3.34 mmol, 1.50 equiv),3-{[(tert-butoxy)carbonyl]amino}propanoic acid (422 mg, 2.23 mmol, 1.00equiv) in DMF (5 mL) was stirred for 1 h at room temperature. Theresulting solution was purified by C18 reverse phase chromatographyeluting with H₂O/CH₃CN to afford 620 mg (78%) of the title compound as awhite solid. LCMS (ESI, m/z): 360.20 [M+H]⁺

Step 2: Synthesis of6-[4-(3-aminopropanoyl)piperazin-1-yl]pyridine-3-carbonitrilehydrochloride

A solution of tert-butylN-[3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-3-oxopropyl]carbamate (610mg, 1.70 mmol, 1.00 equiv) in hydrogen chloride/dioxane (5 mL, 1.00equiv) was stirred for 30 min at room temperature. The resultingsolution was concentrated under vacuum to afford 260 mg (52%) of thetitle compound as a white solid. LCMS (ESI, m/z): 260.14[M+H]⁺

Step 3: Synthesis of 2-[(2S)-pyrrolidin-2-yl]acetic Acid Hydrochloride

A solution of 2-[(2S)-1-[(tert-butoxy)carbonyl]pyrrolidin-2-yl]aceticacid (200 mg, 0.87 mmol, 1.00 equiv) in hydrogen chloride/dioxane (5 mL)was stirred for 30 min at room temperature. The resulting mixture wasconcentrated under vacuum to afford 160 mg (crude) of the title compoundas a white solid. LCMS (ESI, m/z): 130.08 [M+H]⁺

Step 4: Synthesis of2-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]aceticAcid

A solution of 2-(pyrrolidin-2-yl)acetic acid hydrochloride (160 mg, 0.97mmol, 1.00 equiv), Int-A6 (319 mg, 0.97 mmol, 1.00 equiv), TEA (195 mg,1.93 mmol, 2.00 equiv) in ethanol (5 mL) was stirred for 2 h at 80° C.The reaction mixture was concentrated under vacuum, the residue wasapplied onto a silica gel column eluting with DCM/methanol (9/1) toafford 320 mg (79%) of the title compound as yellow oil. LCMS (ESI,m/z): 422.16 [M+H]⁺

Step 5: Synthesis of2-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]aceticAcid

A solution of2-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]aceticacid (310 mg, 0.74 mmol, 1.00 equiv) in hydrogen chloride/dioxane (5 mL)was stirred for 2 h at room temperature. After concentration, theresidue was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN to afford 80 mg (37%) of the title compound as a white solid.LCMS (ESI, m/z): 292.08 [M+H]⁺

Step 6: Synthesis ofN-[3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-3-oxopropyl]-2-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]acetamide

A solution of2-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]aceticacid (60 mg, 0.21 mmol, 1.00 equiv), DIEA (80 mg, 0.62 mmol, 3.00equiv), HOBT (42 mg, 0.31 mmol, 1.50 equiv), EDCI (59.4 mg, 0.31 mmol,1.50 equiv),6-[4-(3-aminopropanoyl)piperazin-1-yl]pyridine-3-carbonitrilehydrochloride (122 mg, 0.41 mmol, 2.00 equiv) in DMF (2 mL) was stirredfor 12 h at room temperature. The resulting solution was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN. Then the residuewas further purified by Prep-HPLC yielding the title compound amide(30.2 mg, 28%) as a white solid. LCMS (ESI, m/z): 533.52 [M+H]⁺, ¹H NMR(400 MHz, DMSO-d₆) δ: 12.45 (s, 1H), 8.51 (d, J=2.3 Hz, 1H), 8.07 (t,J=5.8 Hz, 1H), 7.96 (s, 1H), 7.89 (dd, J=9.1, 2.3 Hz, 1H), 6.94 (d,J=9.0 Hz, 1H), 4.52 (t, J=6.7 Hz, 1H), 3.72-3.66 (m, 4H), 3.58-3.49 (m,5H), 3.27-3.20 (m, 3H), 2.51-2.41 (m, 3H), 2.26 (dd, J=13.9, 7.9 Hz,1H), 2.17-2.09 (m, 1H), 1.89 (s, 1H), 1.79-1.65 (m, 2H).

Example 133:6-[4-(3-[[(2S,4S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-4-(trifluoromethyl)pyrrolidin-2-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl(2S,4S)-2-(hydroxymethyl)-4-(trifluoromethyl)pyrrolidine-1-carboxylate

Under nitrogen, A solution of(2S,4S)-1-[(tert-butoxy)carbonyl]-4-(trifluoromethyl)pyrrolidine-2-carboxylicacid (1.5 g, 5.30 mmol, 1.00 equiv) and BH3THF (7 mL, 4.00 equiv, 1M) inTHF (20 mL) was stirred for 2 h at room temperature, and then thereaction was then quenched by the addition of 20 mL of water, extractedwith 4×20 mL of EtOAc and the organic layers combined, washed with 1×20mL of brine, dried over anhydrous sodium sulfate and concentrated undervacuum to afford 1.35 g of the title compound as crude yellow oil. LCMS(ESI, m/z): 270.12 [M+H]⁺.

Step 2: Synthesis of[(2S,4S)-4-(trifluoromethyl)pyrrolidin-2-yl]methanol hydrochloride

A solution of tert-butyl(2S,4S)-2-(hydroxymethyl)-4-(trifluoromethyl)pyrrolidine-1-carboxylate(1.35 g, 5.01 mmol, 1.00 equiv) in hydrogen chloride/dioxane (15 mL, 4M)was stirred for 1.5 h at room temperature, and then the resultingsolution was concentrated under vacuum to afford 1.2 g of the titlecompound as yellow oil. LCMS (ESI, m/z): 170.07 [M+H]⁺.

Step 3: Synthesis of5-[(2S,4S)-2-(hydroxymethyl)-4-(trifluoromethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of [(2S,4S)-4-(trifluoromethyl)pyrrolidin-2-yl]methanolhydrochloride (1.1 g, 5.35 mmol, 1.00 equiv), TEA (1.08 g, 10.67 mmol,2.00 equiv) and Int-A6 (1.76 g, 5.35 mmol, 1.00 equiv) in ethanol (15mL) was stirred for 1 h at 60° C., and then the resulting solution wasconcentrated under vacuum and then the residue was applied onto a silicagel column eluting with EtOAc/petroleum ether (1;3) to afford 1.3 g(53%) of the title compound as a light brown solid. LCMS (ESI, m/z):462.16 [M+H]⁺.

Step 4: Synthesis of methyl3-[[(2S,4S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-4-(trifluoromethyl)pyrrolidin-2-yl]methoxy]propanoate

A solution of5-[(2S,4S)-2-(hydroxymethyl)-4-(trifluoromethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(600 mg, 1.30 mmol, 1.00 equiv), Cs₂CO₃ (1.27 g, 3.90 mmol, 3.00 equiv)and methyl prop-2-enoate (559 mg, 6.49 mmol, 5.00 equiv) in MeCN (15 mL)was stirred for 3 h at room temperature, and then the resulting solutionwas concentrated under vacuum and then the residue was applied onto asilica gel column eluting with EtOAc/petroleum ether (1:3) to afford 374mg (53%) the title compound as light yellow oil. LCMS (ESI, m/z): 548.19[M+H]⁺.

Step 5: Synthesis of methyl3-[[(2S,4S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-4-(trifluoromethyl)pyrrolidin-2-yl]methoxy]propanoate

A solution of methyl3-[[(2S,4S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-4-(trifluoromethyl)pyrrolidin-2-yl]methoxy]propanoate(374 mg, 0.68 mmol, 1.00 equiv) and TFA (1 mL) in DCM (5 mL) was stirredfor 1 h at room temperature, and then the resulting solution wasconcentrated under vacuum to afford 250 mg of the title compound aslight crude yellow oil. LCMS (ESI, m/z): 418.11 [M+H]⁺.

Step 6: Synthesis of3-[[(2S,4S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-4-(trifluoromethyl)pyrrolidin-2-yl]methoxy]propanoicAcid

A solution of methyl3-[[(2S,4S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-4-(trifluoromethyl)pyrrolidin-2-yl]methoxy]propanoate(250 mg, 0.60 mmol, 1.00 equiv) and LiOH (76 mg, 3.17 mmol, 3.00 equiv)in THF (10 mL) and water (2 mL) was stirred for 1 h at room temperature,and then the resulting solution was diluted with 3 mL of water,extracted with 2×5 mL of EtOAc and the aqueous layers combined, and thepH value of the aqueous layers was adjusted to 4 with hydrogen chloride(1 M), and then the resulting aqueous was extracted with 2×5 mL of EtOAcand the organic layers combined, dried over anhydrous sodium sulfate andconcentrated under vacuum to afford 180 mg of the title compound aslight crude yellow oil. LCMS (ESI, m/z): 404.10 [M+H]⁺.

Step 7: Synthesis of6-[4-(3-[[(2S,4S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-4-(trifluoromethyl)pyrrolidin-2-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-[[(2S,4S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-4-(trifluoromethyl)pyrrolidin-2-yl]methoxy]propanoicacid (170 mg, 0.42 mmol, 1 equiv), DIEA (163.4 mg, 1.26 mmol, 3.00equiv), HATU (160.3 mg, 0.42 mmol, 1.00 equiv) and Int-A4 (87.3 mg, 0.46mmol, 1.10 equiv) in DMF (10 mL) was stirred for 40 min at roomtemperature, and then the resulting solution was extracted with 3×50 mlof EtOAc, washed with 3×50 ml of brine and the organic layers combined,dried over anhydrous sodium sulfate and concentrated under vacuum, andthen the residue was purified by Prep-HPLC yielding the title compound(25.1 mg, 10.38%) as a white solid. LCMS (ESI, m/z): 574.05 [M+H]⁺.¹HNMR: (CD3OD, 400 MHz): δ 8.42 (d, J=2.0 Hz, 1H), 8.10 (s, 1H), 7.77(dd, J=9.2, 2.4 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 4.74 (dt, J=11.0, 5.5Hz, 1H), 3.79-3.61 (m, 12H), 3.53-3.47 (m, 2H), 3.08 (d, J=7.6 Hz, 1H),2.64 (dd, J=11.6, 5.2 Hz, 2H), 2.43-2.40 (m, 1H), 1.92 (td, J=12.2, 8.3Hz, 1H).

Example 134:(S)-3-(4-(5-cyanopyridin-2-yl)piperazin-1-yl)-N-((1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methyl)propanamide

Step 1: Synthesis of ethyl3-(4-(5-cyanopyridin-2-yl)piperazin-1-yl)propanoate

A solution of ethyl prop-2-enoate (600 mg, 5.99 mmol, 1.20 equiv),Int-A4 (940 mg, 4.99 mmol, 1.00 equiv) in ethanol (10 mL) was stirredfor 5.5 h at 80° C. The resulting solution was concentrated under vacuumto afford 1.29 g crude of the title compound as white oil. LCMS (ESI,m/z): 289.16 [M+H]⁺

Step 2: Synthesis of 3-(4-(5-cyanopyridin-2-yl)piperazin-1-yl)propanoicAcid

A solution of ethyl 3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]propanoate(1.56 g, 5.41 mmol, 1.00 equiv), LiOH (648 mg, 27.06 mmol, 5.00 equiv),water (3 mL) in methanol (15 mL) was stirred for 2 h at roomtemperature. The pH value of the solution was adjusted to 5 withhydrogen chloride. The residue was applied onto a silica gel columneluting with DCM/methanol (10:1) to afford 687 mg (49%) of the titlecompound as a white solid LCMS (ESI, m/z): 261.13 [M+H]⁺

Step 3: Synthesis of5-[(2S)-2-(azidomethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1 g, 2.54 mmol, 1.00 equiv), DPPA (1.4 g, 5.09 mmol, 2.00 equiv), DBU(772.6 mg, 5.07 mmol, 2.00 equiv) in toluene (15 mL) was stirred for 6 hat 100° C. After concentrated under vacuum, The residue was applied ontoa silica gel column eluting with EtOAc/petroleum ether (1:1) to afford 1g (94%) of the title compound as yellow oil. LCMS (ESI, m/z): 419.18[M+H]⁺

Step 4: Synthesis of5-[(2S)-2-(aminomethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[(2S)-2-(azidomethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1 g, 2.39 mmol, 1.00 equiv), Palladium carbon (200 mg) in methanol (15mL) was stirred for 0.5 h at room temperature under H₂ atmosphere. Thesolids were filtered out. The resulting solution was concentrated undervacuum to afford 864 mg crude of the title compound as black oil. LCMS(ESI, m/z): 393.19 [M+H]⁺

Step 5: Synthesis of(S)-3-(4-(5-cyanopyridin-2-yl)piperazin-1-yl)-N-((1-(6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methyl)propanamide

A solution of 3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]propanoic acid(220.22 mg, 0.85 mmol, 1.10 equiv),5-[(2S)-2-(aminomethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(300 mg, 0.76 mmol, 1.00 equiv), HATU (441 mg, 1.16 mmol, 1.50 equiv),DIEA (298 mg, 2.31 mmol, 3.00 equiv) in DMF (3 mL) was stirred for 2 hat room temperature. After concentration, the residue was purified byC18 reverse phase chromatography eluting with H₂O/CH₃CN to afford 224 mg(46%) of the title compound as yellow oil. LCMS (ESI, m/z): 635.30[M+H]⁺

Step 6: Synthesis of(S)-3-(4-(5-cyanopyridin-2-yl)piperazin-1-yl)-N-((1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methyl)propanamide

A solution of3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-N-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methyl]propanamide(202 mg, 0.32 mmol, 1.00 equiv), TFA (2 mL) in DCM (10 mL) was stirredfor 2 h at room temperature. After concentration, the residue waspurified by Prep-HPLC eluting with eluting with H₂O/CH₃CN yielding thetitle compound (105 mg, 65%) as a white solid. LCMS (ESI, m/z): 505.10[M+H]⁺, 1HNMR (Methanol-d₄, 300 MHz) δ:8.41 (dd, J=2.4, 0.7 Hz, 1H),8.25 (s, 1H), 7.74 (dd, J=9.1, 2.4 Hz, 1H), 6.87 (dd, J=9.2, 0.9 Hz,1H), 4.46 (t, J=5.3 Hz, 1H), 3.73 (t, J=5.2 Hz, 5H), 3.48 (dd, J=13.8,4.7 Hz, 1H), 3.38 (d, J=9.2 Hz, 2H), 2.69-2.67 (m, 2H), 2.58 (t, J=5.2Hz, 4H), 2.44 (t, J=7.0 Hz, 2H), 2.35-2.26 (m, 1H), 2.02 (s, 1H),1.89-1.69 (m, 2H).

Example 135:6-[4-[3-([[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methyl]amino)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of6-[4-[3-([[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methyl]amino)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of5-[(2S)-2-(aminomethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(470 mg, 1.20 mmol, 1.00 equiv), DIEA (14.45 mg, 0.11 mmol, 0.10 equiv),6-[4-(prop-2-enoyl)piperazin-1-yl]pyridine-3-carbonitrile (257.5 mg,1.06 mmol, 0.95 equiv) in i-propanol (10 mL) was stirred for 20 h at100° C. After concentration, the residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (1:1) to afford 410 mg (54%)of the title compound as brown oil. LCMS (ESI, m/z): 635.31[M+H]⁺

Step 2: Synthesis of6-[4-[3-([[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methyl]amino)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-[3-([[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methyl]amino)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile(400 mg, 0.63 mmol, 1.00 equiv), TFA (3 mL) in DCM (15 mL) was stirredfor 1 h at room temperature. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CNyielding the title compound (46 mg, 14%) as a white solid. LCMS (ESI,m/z): 505.10 [M+H]+, ¹HNMR (300 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.52 (d,J=2.3 Hz, 1H), 8.04 (s, 1H), 7.89 (d, J=9.1 Hz, 1H), 6.94 (d, J=9.1 Hz,1H), 4.34 (d, J=6.7 Hz, 1H), 3.86-3.60 (m, 4H), 3.56-3.50 (m, 5H), 3.20(d, J=11.0 Hz, 1H), 2.88-2.53 (m, 4H), 2.49-2.43 (m, 2H), 2.13 (s, 1H),1.90 (s, 1H), 1.67-1.60 (m, 2H).

Example 136:(S)-6-(4-(3-(methyl((1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methyl)amino)propanoyl)piperazin-1-yl)nicotinonitrile

Step 1: Synthesis of (S)-tert-butyl2-((3-(4-(5-cyanopyridin-2-yl)piperazin-1-yl)-3-oxopropylamino)methyl)pyrrolidine-1-carboxylate

A solution of 6-(4-acryloylpiperazin-1-yl)nicotinonitrile (500 mg, 2.07mmol, 1.00 equiv), DIEA (26.7 mg, 0.21 mmol, 0.10 equiv), (S)-tert-butyl2-(aminomethyl)pyrrolidine-1-carboxylate (454.5 mg, 2.27 mmol, 1.10equiv) in i-PrOH (10 ml) was stirred for 15 h at 100° C. Afterconcentration, the residue was applied onto a silica gel column elutingwith EtOAc/petroleum ether (1:1) to afford 700 mg (76.7%) of the titlecompound as white oil. LCMS (ESI, m/z): 443.28 [M+H]+

Step 2: Synthesis of (S)-tert-butyl2-(((3-(4-(5-cyanopyridin-2-yl)piperazin-1-yl)-3-oxopropyl)(methyl)amino)methyl)pyrrolidine-1-carboxylate

A solution of (S)-tert-butyl2-((3-(4-(5-cyanopyridin-2-yl)piperazin-1-yl)-3-oxopropylamino)methyl)pyrrolidine-1-carboxylate(511 mg, 1.15 mmol, 1.00 equiv), (HCHO)n (312 mg, 3.00 equiv), aceticacid (0.5 mL), NaBH3CN (218.6 mg, 3.48 mmol, 3.00 equiv) in methanol (20mL) was stirred for 20 h at room temperature. After concentration, theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (40:60) to afford 500 mg (95%) of the titlecompound as a white solid. LCMS (ESI, m/z): 457.29[M+H]+

Step 3: Synthesis of(S)-6-(4-(3-(methyl(pyrrolidin-2-ylmethyl)amino)propanoyl)piperazin-1-yl)nicotinonitrile

A solution of (S)-tert-butyl2-(((3-(4-(5-cyanopyridin-2-yl)piperazin-1-yl)-3-oxopropyl)(methyl)amino)methyl)pyrrolidine-1-carboxylate(500 mg, 1.10 mmol, 1.00 equiv) in hydrogen chloride-dioxane (20 mL) wasstirred for 1 h at room temperature. The resulting mixture wasconcentrated under vacuum to afford 400 mg crude of the title compoundas brown solid. LCMS (ESI, m/z): 357.24 [M+H]+

Step 4: Synthesis of(S)-6-(4-(3-(methyl((1-(6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methyl)amino)propanoyl)piperazin-1-yl)nicotinonitrile

A solution of(S)-6-(4-(3-(methyl(pyrrolidin-2-ylmethyl)amino)propanoyl)piperazin-1-yl)nicotinonitrile(400 mg, 1.12 mmol, 1.00 equiv), TEA (339.4 mg, 3.35 mmol, 3.00 equiv),Int-A6 (479 mg, 1.46 mmol, 1.30 equiv) in ethanol (20 mL) was stirredfor 3 h at 70° C. After concentration, the residue was applied onto asilica gel column eluting with EtOAc/petroleum ether (80:20) to afford980 mg crude of the title compound as a yellow solid. LCMS (ESI, m/z):649.33 [M+H]+

Step 5: Synthesis of(S)-6-(4-(3-(methyl((1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methyl)amino)propanoyl)piperazin-1-yl)nicotinonitrile

A solution of(S)-6-(4-(3-(methyl((1-(6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methyl)amino)propanoyl)piperazin-1-yl)nicotinonitrile(900 mg, 1.39 mmol, 1.00 equiv) in hydrogen chloride/dioxane (20 mL) wasstirred for 1 h at room temperature. After concentration, the residuewas purified by C18 reverse phase chromatography eluting with H₂O/CH3CN.Then the residue was further purified by Prep-HPLC yielding the titlecompound (38 mg, 5%) as a white solid. LCMS (ESI, m/z): 519.10 [M+H]+,¹H NMR (300 MHz, Chloroform-d) δ 10.81 (s, 1H), 8.44 (d, J=2.3 Hz, 1H),7.91 (s, 1H), 7.67 (dd, J=9.0, 2.3 Hz, 1H), 6.64 (d, J=9.1 Hz, 1H), 4.33(q, J=7.5 Hz, 1H), 3.75 (d, J=10.3 Hz, 4H), 3.69 (d, J=5.5 Hz, 3H), 3.58(d, J=6.3 Hz, 2H), 3.47-3.26 (m, 1H), 2.88-2.83 (m, 1H), 2.77-2.70 (m,1H), 2.62-2.38 (m, 4H), 2.31 (s, 4H), 2.15-1.87 (m, 1H), 1.76-1.67 (m,1H), 1.66-1.61 (m, 1H).

Example 137:6-[4-(3-[[(7S)-6-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-7-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrileand6-[4-(3-[[(7R)-6-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-7-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of methyl2-[[(2-chloropyridin-3-yl)methyl]amino]acetate

A solution of methyl 2-aminoacetate hydrochloride (39.89 g, 317.71 mmol,1.50 equiv), 2-chloropyridine-3-carbaldehyde (30 g, 211.93 mmol, 1.00equiv) and TEA (42.9 g, 423.95 mmol, 2.00 equiv) in methanol (200 mL)was stirred for 12h at room temperature, and then NaBH4 (16.17 g, 427.44mmol, 2.00 equiv) was added in, and then the resulting solution wasstirred for another 40 min at room temperature, and then the resultingsolution was quenched by the addition of 250 mL of water, extracted with2×300 mL of EtOAc and the organic layers combined, washed with 1×300 mLof brine, dried over anhydrous sodium sulfate and concentrated undervacuum, and then the residue was applied onto a silica gel columneluting with EtOAc/petroleum ether (3:2) to afford 26.1 g (57%) of thetitle compound as yellow oil. LCMS (ESI, m/z): 215.05 [M+H]⁺.

Step 2: Synthesis of methyl2-[[(tert-butoxy)carbonyl][(2-chloropyridin-3-yl)methyl]amino]acetate

A solution of methyl 2-[[(2-chloropyridin-3-yl)methyl]amino]acetate(26.6 g, 123.9 mmol, 1.00 equiv) and TEA (37.6 g, 371.6 mmol, 3.00equiv) in DCM (200 mL) was stirred for 10 min at room temperature, andthen (Boc)₂O (40.6 g, 186 mmol, 1.50 equiv) was added in, and then theresulting solution was stirred for another 1.5 h at room temperature,the resulting solution was concentrated under vacuum and the residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(1:6) to afford 26.8 g (69%) of the title compound as yellow oil. LCMS(ESI, m/z): 315.05 [M+H]⁺.

Step 3: Synthesis of 6-tert-butyl 7-methyl5H,6H,7H-pyrrolo[3,4-b]pyridine-6,7-dicarboxylate

Under nitrogen, a solution of methyl2-[[(tert-butoxy)carbonyl][(2-chloropyridin-3-yl)methyl]amino]acetate (4g, 12.71 mmol, 1.00 equiv), Pd(PPh3)4 (1.47 g, 1.27 mmol, 0.10 equiv),K3PO4 (8.1 g, 3.00 equiv) and PhOH (358 mg, 0.30 equiv) in DMF (75 mL)was stirred for 2.5h at 90° C., and then the resulting solution wasdiluted with 100 mL of EA, washed with 3×80 mL of H₂O, dried overanhydrous sodium sulfate, concentrated under vacuum and then the residuewas applied onto a silica gel column eluting with EtOAc/petroleum ether(1:3) to afford 620 mg (18%) of the title compound as light yellow oil.LCMS (ESI, m/z): 279.13 [M+H]⁺.

Step 4: Synthesis of Tert-Butyl7-(hydroxymethyl)-5H,6H,7H-pyrrolo[3,4-b]pyridine-6-carboxylate

A solution of 6-tert-butyl 7-methyl5H,6H,7H-pyrrolo[3,4-b]pyridine-6,7-dicarboxylate (1.46 g, 5.25 mmol,1.00 equiv) and LAH (597 mg, 17.6 mmol, 3.00 equiv) in THF (60 mL) wasstirred for 0.5 h at room temperature, and then the resulting solutionwas quenched by the addition of 2 mL of water and 2 mL of 20% aqueous ofNaOH, and then the mixture was dried over anhydrous sodium sulfate, andthen the resulting solution was concentrated under vacuum and then theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (7:3) to afford 210 mg (16%) of the title compoundas an orange solid. LCMS (ESI, m/z): 251.13 [M+H]⁺.

Step 5: Synthesis of [5H,6H,7H-pyrrolo[3,4-b]pyridin-7-yl]methanolHydrochloride

A solution of tert-butyl7-(hydroxymethyl)-5H,6H,7H-pyrrolo[3,4-b]pyridine-6-carboxylate (210 mg,0.84 mmol, 1.00 equiv) in hydrogen chloride/dioxane (10 mL, 4M) wasstirred for 1 h at room temperature, and then the resulting solution wasconcentrated under vacuum to afford 156 mg (crude) of the title compoundas a brown solid. LCMS (ESI, m/z): 151.08 [M+H]⁺.

Step 6: Synthesis of5-[7-(hydroxymethyl)-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of [5H,6H,7H-pyrrolo[3,4-b]pyridin-7-yl]methanolhydrochloride (500 mg, 3.33 mmol, 1.00 equiv), Int-A6 (1.08 g, 3.28mmol, 1.00 equiv) and TEA (1 g, 9.88 mmol, 3.00 equiv) in ethanol (25mL) was stirred for 1 h at 60° C., and then the resulting solution wasconcentrated under vacuum and then the residue was applied onto a silicagel column eluting with EtOAc/petroleum ether (8:2) to afford 464 mg(31%) of the title compound as a brown solid. LCMS (ESI, m/z): 443.16[M+H]⁺.

Step 7: Synthesis of methyl3-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-7-yl]methoxy)propanoate

A solution of5-[7-(hydroxymethyl)-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(270 mg, 0.61 mmol, 1.00 equiv), Cs₂CO₃ (595 mg, 1.83 mmol, 3.00 equiv)and methyl prop-2-enoate (157 mg, 1.82 mmol, 3.00 equiv) in MeCN (12 mL)was stirred for 18 h at room temperature, and then the resultingsolution was diluted with 20 mL of EtOAc, washed with 3×15 mL of H₂O,and the organic layers was dried over anhydrous sodium sulfate andconcentrated under vacuum, and then the residue was applied onto asilica gel column with EtOAc/petroleum ether (67:33) to afford 114 mg(35%) of the title compound as a colorless solid. LCMS (ESI, m/z):529.20 [M+H]⁺.

Step 8: Synthesis of3-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-7-yl]methoxy)propanoicAcid

A solution of methyl3-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-7-yl]methoxy)propanoate(540 mg, 1.02 mmol, 1.00 equiv) and LiOH.H₂O (214 mg, 5.10 mmol, 5.00equiv) in methanol (5 mL) and water (1 mL) was stirred for 2 h at roomtemperature, and then the pH value of the solution was adjusted to 5with hydrogen chloride (12 M), and then the resulting solution wasconcentrated under vacuum to afford 420 mg of the title compound asacrude brown solid. LCMS (ESI, m/z): 515.19 [M+H]⁺.

Step 9: Synthesis of3-([6-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-7-yl]methoxy)propanoicAcid

A solution of3-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-7-yl]methoxy)propanoicacid (460 mg, 0.89 mmol, 1.00 equiv) and TFA (5 mL) in DCM (20 mL) wasstirred for 1 h at room temperature, and then the resulting solution wasconcentrated under vacuum to afford 344 mg of the title compound ascrude brown oil. LCMS (ESI, m/z): 385.10 [M+H]⁺.

Step 10: Synthesis of6-[4-(3-[[(7S)-6-[6-oxo-5-(trifluoromethyl-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-7-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrileand6-[4-(3-[[(7R)-6-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-7-yl]methoxy]propanol)piperazin-1-yl]pyridine-3-carbonitrile

A solution of placed3-([6-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-7-yl]methoxy)propanoicacid (344 mg, 0.90 mmol, 1.00 equiv), HATU (339 mg, 0.89 mmol, 1.00equiv), DIEA (576 mg, 4.46 mmol, 5.00 equiv) and Int-A4 (232 mg, 0.89mmol, 1.00 equiv) in DMF (4 mL) was stirred for 1 h at room temperature,and then the residue was purified by C18 reverse phase chromatographyeluting with H₂O/CH₃CN, after concentration, and then the residue wasfurther purified by Prep-HPLC and Chiral-Prep-HPLC yielding the titlecompounds. The absolute stereochemistry was assigned based on a proteinX-ray crystal structure obtained of Example 18 Isomer B which confirmed(S)-absolute stereochemistry and was observed to be the more potentenantiomer.

Isomer A (39.8 mg, 30%) as a white solid. LCMS (ESI, m/z): 555.10[M+H]⁺, ¹HNMR (Methanol-d4, 300 MHz) δ 8.50 (d, J=3.9 Hz, 1H), 8.45 (s,1H), 8.29 (s, 1H), 7.82-7.76 (m, 2H), 7.38 (dd, J=8.4, 5.1 Hz, 1H), 6.89(d, J=8.7 Hz, 1H), 5.78 (t, J=3.0 Hz, 1H), 5.28 (d, J=14.7 Hz, 1H), 4.70(d, J==14.7 Hz, 1H), 4.10 (dd, J=10.2, 2.7 Hz, 1H), 3.87-3.54 (m, 11H),2.61 (dd, J=10.5, 5.4 Hz, 2H), tR=4.838 min (CHIRALPAK IC-3, 0.46*10 cm;3 um, MtBE (0.1% DEA):EtOH=70:30, 1.0 mL/min) and isomer B (38.1 mg,29%) as a white solid. LCMS (ESI, m/z): 555.10 [M+H]⁺, tR=5.930 min(CHIRALPAK IC-3, 0.46*10 cm; 3 um, MtBE (0.1% DEA):EtOH=70:30, 1.0mL/min).

Example 138:3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-N-methyl-N-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methyl]propanamide

Step 1: Synthesis of5-[(2S)-2-[(methylamino)ethyl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[(2S)-2-(aminomethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(570 mg, 1.45 mmol, 1.00 equiv), potassium hydroxide (15 mg, 0.27 mmol,0.20 equiv), CH₂O (47 mg, 1.57 mmol, 1.20 equiv), NaBH₄ (100 mg, 2.64mmol, 2.00 equiv) in methanol (20 mL) was stirred for 4 h at 50° C. inan oil bath. The resulting solution was extracted with 2×200 mL of DCMand the organic layers combined and concentrated under vacuum. Theresidue was applied onto a silica gel column eluting with DCM/methanol(96:4) to afford 380 mg (64%) of the title compound as yellow oil. LCMS(ESI, m/z): 407.20 [M+H]⁺

Step 2: Synthesis of3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-N-methyl-N-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methyl]propanamide

A solution of 3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]propanoic acid(248 mg, 0.95 mmol, 1.00 equiv), DIEA (368 mg, 2.85 mmol, 3.00 equiv),HATU (365 mg, 0.96 mmol, 1.02 equiv),5-[(2S)-2-[(methylamino)methyl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(386 mg, 0.95 mmol, 1.00 equiv) in DMF (3 mL) was stirred for 1 h at 25°C. After concentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN (15:85) to afford 300 mg of thetitle compound as yellow oil. LCMS (ESI, m/z): 649.32 [M+H]⁺

Step 3: Synthesis of3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-N-methyl-N-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methyl]propanamide

A solution of3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-N-methyl-N-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methyl]propanamide(300 mg, 0.46 mmol, 1.00 equiv), a solution of TFA/DCM (12 mL) in DCM(10 mL) was stirred for 1 h at 25° C. The pH value of the solution wasadjusted to 8 with NH₂CH₂CH₂OH. The crude product (150 mg) was purifiedby Flash-Prep-HPLC yielding the title compound (97.9 mg 41%) as a whitesolid. LCMS (ESI, m/z): 519.24 [M+H]⁺, ¹H NMR (Methanol-d₄, 400 MHz) δ:8.41 (d, J=2.0 Hz, 1H), 8.24 (s, 1H), 7.75-7.73 (m, 1H), 6.87-6.85 (m,1H), 4.63-4.60 (m, 1H), 3.74-3.72 (m, 6H), 3.40-3.37 (m, 1H), 3.31-3.29(m, 1H), 3.14 (s, 3H), 2.74-2.70 (m, 2H), 2.68-2.53 (m, 6H), 2.32-2.27(m, 1H), 2.06-2.05 (m, 1H), 1.85-1.76 (m, 2H)

Example 139:6-[4-(3-[[(2S)-4-(methoxymethyl)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of 1-tert-butyl 2-methyl(2S)-4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate

A solution of 1-tert-butyl 2-methyl(2S)-4-methylidenepyrrolidine-1,2-dicarboxylate (5 g, 20.72 mmol, 1.00equiv), BH₃SMe₂ (3.47 g, 2.20 equiv), sodium hydroxide (1.05 g, 26.25mmol, 1.25 equiv), water (20 mL), H₂O₂ (2.14 g, 3.00 equiv) in THF (100mL) was stirred for 5 h at room temperature. The resulting solution wasquenched with H₂O. The resulting solution was extracted with 5×20 mL ofEtOAc and the organic layers combined. The residue was applied onto asilica gel column eluting with EtOAc/petroleum ether (1:1) to afford 2.5g (47%) of the title compound as a red solid. LCMS (ESI, m/z): 260.15[M+H]+

Step 2: Synthesis of(2S)-1-[(tert-butoxy)carbonyl]-4-(methoxymethyl)pyrrolidine-2-carboxylicacid

A solution of 1-tert-butyl 2-methyl(2S)-4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (1.5 g, 5.78 mmol,1.00 equiv), sodium hydride (461.6 g, 19.23 mol, 2.00 equiv), MeI (4.1g, 5.00 equiv) in THF (25 mL) was stirred for 3 h at room temperature.The resulting solution was quenched with H₂O and the resulting solutionwas extracted with 5×20 mL of EtOAc and the organic layers combined. Theresidue was applied onto a silica gel column eluting with DCM/methanol(15:85) to afford 1.1 g (73%) of the title compound as a white solid.LCMS (ESI, m/z): 260.15[M+H]+

Step 3: Synthesis of Tert-Butyl(2S)-2-(hydroxymethyl)-4-(methoxyethyl)pyrrolidine-1-carboxylate

A solution of diborane (1.37 g, 15.94 mmol, 1.00 equiv),(2S)-1-[(tert-butoxy)carbonyl]-4-(methoxymethyl)pyrrolidine-2-carboxylicacid (15 mL) in was stirred for 3 h at room temperature. The resultingsolution was quenched with H₂O. The resulting solution was extractedwith 3×20 mL of EtOAc and the organic layers combined. The resultingmixture was concentrated under vacuum to afford 1.3 g (33%) of the titlecompound as brown oil. LCMS (ESI, m/z): 246.17[M+H]+

Step 4: Synthesis of [(2S)-4-(methoxymethyl)pyrrolidin-2-yl]methanol

A solution of tert-butyl(2S)-2-(hydroxymethyl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (1.3g, 5.30 mmol, 1.00 equiv) in hydrogen chloride-1,4dioxane (15 mL) wasstirred for 1 h at room temperature. The resulting mixture wasconcentrated under vacuum to afford 1 g (crude) of the title compound asbrown oil. LCMS (ESI, m/z): 146.12 [M+H]+

Step 5: Synthesis of5-[(2S)-2-(hydroxymethyl)-4-(methoxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of [(2S)-4-(methoxymethyl)pyrrolidin-2-yl]methanol (760 mg,5.23 mmol, 1.00 equiv), TEA (1.69 g, 16.70 mmol, 3.00 equiv), Int-A6(1.72 g, 5.23 mmol, 1.00 equiv) in ethanol (15 mL) was stirred for 2 hat 60° C. The resulting solution was quenched with H₂O. The solution wasextracted with EtOAc (3×50 mL) and the organic layers combined. Thesolution was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1:1) to afford 375 mg (16%) of the title compoundas a yellow solid. LCMS (ESI, m/z): 438.21 [M+H]⁺

Step 6: Synthesis of Tert-Butyl3-[[(2S)-4-(methoxymethyl)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoate

A solution of Cs₂CO₃ (312.5 mg, 0.96 mmol, 1.50 equiv),5-[(2S)-2-(hydroxymethyl)-4-(methoxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[2-(trimethylsilyl)ethoxy]methyl-2,3-dihydropyridazin-3-one(280 mg, 0.64 mmol, 1.00 equiv), tert-butyl prop-2-enoate (410 mg, 3.20mmol, 5.00 equiv) in MeCN (15 mL) in was stirred for 20 h at 40° C. Theresulting mixture was concentrated under vacuum and the residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(1:1) to afford 152 mg (42%) of the title compound as brown oil. LCMS(ESI, m/z): 566.29 [M+H]⁺

Step 7: Synthesis of3-[[(2S)-4-(methoxymethyl)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoic

A solution of tert-butyl3-[[(2S)-4-(methoxymethyl)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoate(140 mg, 0.25 mmol, 1.00 equiv), TFA (2 mL) in DCM (10 mL) was stirredfor 1 h at room temperature. The resulting mixture was concentratedunder vacuum and the residue was applied onto a silica gel columneluting with DCM/methanol (10:1) to afford 90 mg (96%) of the titlecompound as brown oil. LCMS (ESI, m/z): 380.15 [M+H]⁺

Step 8: Synthesis of6-[4-(3-[[(2S)-4-(methoxymethyl)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-[[(2S)-4-(methoxymethyl)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]propanoicacid (78 mg, 0.21 mmol, 1.00 equiv), EDC/HCl (99 mg, 2.50 equiv),4-dimethylaminopyridine (50.3 mg, 0.41 mmol, 2.00 equiv), Int-A4 (46.4mg, 0.25 mmol, 1.20 equiv) in DMF (3 mL) was stirred for 2 h at 60° C.After concentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN. Then the residue was furtherpurified by Prep-HPLC yielding the title compound (6.1 mg, 5%) as awhite solid. LCMS (ESI, m/z): 550.20 [M+H]+, 1H NMR (300 MHz,Methanol-d4) δ 8.45 (d, J=2.3 Hz, 1H), 8.13 (d, J=2.9 Hz, 1H), 7.79 (dd,J=9.1, 2.4 Hz, 1H), 6.89 (d, J=9.1 Hz, 1H), 4.66 (d, J=7.6 Hz, 1H),3.87-3.60 (m, 11H), 3.54-3.40 (m, 3H), 3.36 (s, 3H), 3.27 (s, 1H),3.25-3.08 (m, 1H), 2.64-2.62 (m, 2H), 2.58-1.39 (m, 3H)

Example 140:6-(4-[3-[(1R)-1-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]ethoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrileand6-(4-[3-[(1S)-1-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]ethoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1: Synthesis of(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidine-2-carboxylicAcid

A solution of Int-A6 (3.28 g, 9.98 mmol, 1 equiv),(2S)-pyrrolidine-2-carboxylic acid (1.15 g, 9.99 mmol, 1.00 equiv), TEA(2.02 g, 19.96 mmol, 2.00 equiv) in MeCN (20 mL) was stirred for 3 hr at60° C. The solids were filtered out after the resulting solution werecooled to room temperature. The resulting mixture was concentrated. Thisresulted in 3.91 g (96.19%) of the title compound as yellow oil. LCMS(ESI, m/z): 408.15 [M+H]⁺

Step 2: Synthesis of(2S)—N-methoxy-N-methyl-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidine-2-carboxamide

A solution of(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidine-2-carboxylicacid (3.91 g, 9.60 mmol, 1 equiv), SOCl2 (1.4 mL, 11.70 mmol, 2 equiv)in DCM (20 mL) was stirred for 2 hr at room temperature. Then theresulting solution was concentrated and dissolved in DCM (30 mL), thenmethoxy(methyl)amine hydrochloride (1.9 g, 19.19 mmol, 2 equiv) and TEA(2.9 g, 28.79 mmol, 3 equiv) were added. The resulting solution wasallowed to react, with stirring, for an additional 1 hr at roomtemperature. The resulting mixture was washed with 2×10 of H₂O. Thenorganic were combined and concentrated. The residue was applied onto asilica gel column with EtOAc/petroleum ether (1/2). This resulted in2.02 g (46.7%) of the title compound as yellow oil. LCMS (ESI, m/z):451.19 [M+H]⁺

Step 3: Synthesis of5-[(2S)-2-acetylpyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of(2S)—N-methoxy-N-methyl-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidine-2-carboxamide(2.02 g, 4.48 mmol, 1 equiv) in THF (30 mL) maintained with an inertatmosphere of nitrogen. This was followed by the addition of a solutionof bromo(methyl)magnesium (4.5 mL, 37.60 mmol, 3.00 equiv) in THF (mL).The resulting solution was stirred for 4 hr at room temperature. Thereaction was then quenched by the addition of 50 mL of water. Theresulting solution was extracted with 3×50 ml of EtOAc and the organiclayers was concentrated. The residue was applied onto a silica gelcolumn with EtOAc/petroleum ether (1/2). This resulted in 1.434 g(78.88%) of the title compound as yellow oil. LCMS (ESI, m/z): 406.17[M+H]⁺

Step 4: Synthesis of5-[(2S)-2-(1-hydroxyethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[(2S)-2-acetylpyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1.434 g, 3.54 mmol, 1 equiv), CaCl2 (784 mg, 7.06 mmol, 2.00 equiv),NaBH₄ (268 mg, 7.08 mmol, 2.00 equiv) in THF (20 mL) was stirred for 2hr at room temperature. The solids were filtered out. The resultingmixture was concentrated. The residue was applied onto a silica gelcolumn with EtOAc/petroleum ether (2/3). This resulted in 1.02 g (70.8%)of the title compound as yellow oil. LCMS (ESI, m/z): 408.19 [M+H]⁺

Step 5: Synthesis of Tert-Butyl3-[1-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]ethoxy]propanoate

A solution of5-[(2S)-2-(1-hydroxyethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(600 mg, 1.47 mmol, 1 equiv), tert-butyl prop-2-enoate (941.7 mg, 7.35mmol, 4.99 equiv), Cs₂CO₃ (479.7 mg, 1.47 mmol, 1.00 equiv) in MeCN (10mL) was stirred for 5 hr at 80° C. The solids were filtered out. Theresulting mixture was concentrated. The residue was applied onto asilica gel column with EtOAc/petroleum ether (1/4). This resulted in 190mg (24.1%) of the title compound as yellow oil. LCMS (ESI, m/z): 536.27[M+H]⁺

Step 6: Synthesis of3-[1-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]ethoxy]propanoicacid

A solution of tert-butyl3-[1-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]ethoxy]propanoate(180 mg, 0.34 mmol, 1 equiv) in DCM (3 mL) and TFA (0.5 mL). Theresulting solution was stirred for 3 hr at room temperature. Theresulting mixture was concentrated. The resulting solution was dissolvedin 5 mL NH3(g) in MeOH and allowed to react, with stirring, for anadditional 1 hr at room temperature. The resulting mixture wasconcentrated again. This resulted in 117 mg (99.7%) of the titlecompound as a yellow solid. LCMS (ESI, m/z): 350.12 [M+H]⁺

Step 7: Synthesis of6-(4-[3-[(1R)-1-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]ethoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrileand6-(4-[3-[(1S)-1-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]ethoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of3-[1-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]ethoxy]propanoicacid (117 mg, 0.33 mmol, 1 equiv), Int-A4 (66.2 mg, 0.35 mmol, 1.05equiv), HATU (127.4 mg, 0.33 mmol, 1 equiv), DIEA (129.9 mg, 1.01 mmol,3.00 equiv) in was placed DMF (10 mL) was stirred for 1 overnight atroom temperature. The reaction was then quenched by the addition of 10mL of water. The resulting solution was extracted with 3×10 ml of EtOAcconcentrated. The residue was applied onto a silica gel column withEtOAc/petroleum ether (1/2). Then the residue was further purified byPrep-HPLC and Chiral-Prep-HPLC yielding (after arbitrary assignment ofstereochemistry) the title compounds, respectively, isomer A (15.3 mg,8.79%) as a white solid. LCMS (ESI, m/z): 520.10 [M+H]⁺, ¹HNMR(Methanol-d4, 300 MHz) δ 8.44 (dd, J=2.3, 0.8 Hz, 1H), 8.13 (s, 1H),7.78 (dd, J=9.1, 2.4 Hz, 1H), 6.88 (dd, J=9.1, 0.8 Hz, 1H), 4.36 (q,J=7.9 Hz, 1H), 3.90 (dt, J=9.1, 6.1 Hz, 1H), 3.78-3.63 (m, 7H),3.67-3.48 (m, 3H), 3.37 (d, J=6.1 Hz, 2H), 2.49 (t, J=5.9 Hz, 2H), 2.21(dt, J=13.3, 6.6 Hz, 1H), 1.98 (q, J=5.1, 4.7 Hz, 1H), 1.81-1.52 (m,2H), 1.20 (d, J=6.1 Hz, 3H). tR=3.117 min (CHIRALPAK ID-3, 0.46*10 cm; 3um, MtBE (0.1% DEA):EtOH=70:30, 1.0 mL/min) and isomer B (4.6 mg, 2.64%)as a white solid. LCMS (ESI, m/z): 520.10 [M+H]⁺, ¹H NMR (300 MHz,Methanol-d₄) δ 8.44 (dd, J=2.4, 0.8 Hz, 1H), 8.12 (s, 1H), 7.78 (dd,J=9.1, 2.3 Hz, 1H), 6.88 (dd, J=9.1, 0.9 Hz, 1H), 4.52 (t, J=7.6 Hz,1H), 3.91-3.60 (m, 12H), 3.42 (s, 2H), 2.65 (td, J=6.0, 2.4 Hz, 2H),2.23-2.07 (m, 1H), 2.09-1.82 (m, 2H), 1.70 (dt, J=14.3, 7.4 Hz, 1H),1.16 (d, J=6.3 Hz, 3H). tR=3.770 min (CHIRALPAK ID-3, 0.46*10 cm; 3 um,MtBE (0.1% DEA):EtOH=70:30, 1.0 mL/min).

Example 141:6-(4-[2-[(2S,5S)-5-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile,6-(4-[2-[(2R,5S)-5-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile,6-(4-[2-[(2S,5R)-5-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand6-(4-[2-[(2R,5R)-5-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1: Synthesis of Tert-Butyl(2S)-2-(1-hydroxypent-4-en-1-yl)pyrrolidine-1-carboxylate

Under maintained with an inert atmosphere of nitrogen, A solution oftert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (10 g, 50.19 mmol,1.00 equiv) in THF (50 mL), then the bromo(but-3-en-1-yl)magnesium inTHF (120 mL) (1M, 1.20 equiv) was added to the resulting solution at−10° C., then the resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column eluting with DCM to afford7 g (55%) of the title compound as yellow oil. LCMS (ESI, m/z):256.18[M+H]⁺

Step 2: Synthesis of Tert-Butyl(2S)-2-[(4E)-1-hydroxy-6-oxohex-4-en-1-yl]pyrrolidine-1-carboxylate

A solution of tert-butyl(2S)-2-(1-hydroxypent-4-en-1-yl)pyrrolidine-1-carboxylate (5.1 g, 19.97mmol, 1.00 equiv), Grubbs 2^(nd) generation catalyst (0.85 g, 0.05equiv), (2E)-but-2-enal (7 g, 99.87 mmol, 5.00 equiv) in DCM (30 mL) wasstirred overnight at 50° C. in an oil bath. The resulting mixture wasconcentrated under vacuum and the residue was applied onto a silica gelcolumn eluting with DCM. This resulted in 2.85 g (50%) of the titlecompound as light yellow oil. LCMS (ESI, m/z): 284.18 [M+H]⁺

Step 3: Synthesis of Tert-Butyl(2S)-2-[5-(2-oxoethyl)oxolan-2-yl]pyrrolidine-1-carboxylate

A solution of tert-butyl(2S)-2-[(4E)-1-hydroxy-6-oxohex-4-en-1-yl]pyrrolidine-1-carboxylate(2.83 g, 9.99 mmol, 1.00 equiv), sodium hydride (40 mg, 1.67 mmol, 0.10equiv) in THF (30 mL) was stirred overnight at room temperature. Theresulting mixture was concentrated under vacuum to afford 2.83 g (crude)of the title compound as light yellow oil. LCMS (ESI, m/z): 284.18[M+H]⁺

Step 4: Synthesis of2-[5-[(2S)-1-[(tert-butoxy)carbonyl]pyrrolidin-2-yl]oxolan-2-yl]aceticAcid

A solution of tert-butyl(2S)-2-[5-(2-oxoethyl)oxolan-2-yl]pyrrolidine-1-carboxylate (2.83 g,9.99 mmol, 1.00 equiv), AgNO3 (7.2 g, 4.00 equiv), sodium hydroxide (1.6g, 40.00 mmol, 4.00 equiv) in methanol (20 mL) and water (40 mL) wasstirred for 2 days at room temperature. The solids were filtered out.The pH value of the solution was adjusted to 4 with hydrogen chlorideacquesous (2M). The resulting mixture was concentrated under vacuum. Theresulting mixture was extracted with 100 mL×3 of DCM and the organiclayers combined. This resulted in 0.75 g (25%) of the title compound asa solid. LCMS (ESI, m/z): 300.17 [M+H]⁺

Step 5: Synthesis of Tert-Butyl(2S)-2-(5-[2-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl)pyrrolidine-1-carboxylate

A solution of2-[5-[(2S)-1-[(tert-butoxy)carbonyl]pyrrolidin-2-yl]oxolan-2-yl]aceticacid (300 mg, 1.00 mmol, 1.00 equiv), DIEA (645 mg, 4.99 mmol, 5.00equiv), HATU (260 mg, 0.68 mmol, 2.00 equiv), Int-A4 (450 mg, 2.00 mmol,2.00 equiv) in DMF (10 mL), was stirred overnight at room temperature.The reaction was then quenched by the addition of 100 mL of water. Theresulting solution was extracted with 3×50 mL of EtOAc and the organiclayers combined and concentrated under vacuum. The residue was appliedonto a silica gel column eluting with DCM to afford 200 mg (43%) of thetitle compound as light yellow oil. LCMS (ESI, m/z): 470.27 [M+H]⁺

Step 6: Synthesis of6-[4-(2-[5-[(2S)-pyrrolidin-2-yl]oxolan-2-yl]acetyl)piperazin-1-yl]pyridine-3-carbonitrileHydrochloride

A solution of tert-butyl(2S)-2-(5-[2-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl)pyrrolidine-1-carboxylate(1.1 g, 2.34 mmol, 1.00 equiv) in hydrogen chloride/dioxane (20 mL) wasstirred overnight at 25° C. The resulting mixture was concentrated undervacuum to afford 0.9 g (95%) of the title compound as a yellow solid.LCMS (ESI, m/z): 370.22 [M−Cl]⁺

Step 7: Synthesis of6-[4-(2-[5-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]oxolan-2-yl]acetyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-(2-[5-[(2S)-pyrrolidin-2-yl]oxolan-2-yl]acetyl)piperazin-1-yl]pyridine-3-carbonitrilehydrochloride (900 mg, 2.22 mmol, 1.00 equiv), TEA (670 mg, 6.62 mmol,3.00 equiv), Int-A6 (880 mg, 2.68 mmol, 1.20 equiv) in ethanol (20 mL)was stirred for 2 h at 80° C. in an oil bath. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with DCM to afford 650 mg (44%) of the title compound asyellow oil. LCMS (ESI, m/z): 662.30 [M+H]

Step 8: Synthesis of6-(4-[2-[(2S,5S)-5-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile,6-(4-[2-[(2R,5S)-5-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile,6-(4-[2-[(2S,5R)-5-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand6-(4-[2-[(2R,5R)-5-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-[4-(2-[5-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]oxolan-2-yl]acetyl)piperazin-1-yl]pyridine-3-carbonitrile(650 mg, 0.98 mmol, 1.00 equiv) in DCM (5 mL) and TFA (5 mL) was stirredfor 2 h at room temperature. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/ACN. Theresidue was further purified by Prep-HPLC and Chiral-Prep-HPLC yieldingthe title compounds. The absolute stereochemistry of Isomer B wasassigned based on a protein X-ray crystal structure obtained of Example141 Isomer B, which confirmed the absolute stereochemistry of the morepotent enantiomer. The absolute stereochemistry of the remainingdiastereoisomers A, C, and D was arbitrarily assigned.

Isomer A (29.2 mg, 19%) as a white solid. LCMS (ESI, m/z): 532.30[M+H]⁺, HNMR (400 MHz, DMSO-d₆) δ 12.24 (s, 1H), 8.49 (d, J=2.3 Hz, 1H),8.05 (s, 1H), 7.87 (dd, J=9.1, 2.4 Hz, 1H), 6.88 (d, J=9.1 Hz, 1H), 4.46(q, J=7.8 Hz, 1H), 4.35-4.23 (m, 1H), 3.82 (q, J=7.4 Hz, 1H), 3.70-3.62(m, 3H), 3.52 (d, J=10.2 Hz, 4H), 3.23-3.14 (m, 1H), 2.66 (dd, J=14.8,6.5 Hz, 1H), 2.40 (dd, J=14.8, 6.2 Hz, 1H), 2.19-2.01 (m, 1H), 2.02 (m,2H), 1.90-1.81 (m, 1H), 1.71-1.40 (m, 4H). tR=6.92 min CHIRALPAK ID-3,0.46*10 cm; 3 um, MtBE (0.1% DEA):EtOH=80:20, 1.0 mL/min)

Isomer B (26.9 mg, 18%) as a white solid. LCMS (ESI, m/z): 532.30[M+H]⁺, HNMR (400 MHz, DMSO-d₆) δ12.29 (s, 1H), 8.51 (d, J=2.3 Hz, 1H),8.16 (s, 1H), 7.89 (dd, J=9.1, 2.3 Hz, 1H), 6.93 (d, J=9.0 Hz, 1H), 4.48(q, J=7.6 Hz, 1H), 4.19 (p, J=6.3 Hz, 1H), 3.72 (dd, J=13.0, 6.0 Hz,5H), 3.54 (d, J=6.3 Hz, 7H), 3.25-3.15 (m, 1H), 2.70 (dd, J=15.4, 6.1Hz, 1H), 2.51-2.43 (m, 1H), 2.13-1.95 (m, 2H), 1.90 (tt, J=9.4, 4.6 Hz,2H), 1.71-1.47 (m, 4H). tR=3.95 min CHIRALPAK ID-3, 0.46*10 cm; 3 um,MtBE (0.1% DEA):EtOH=80:20, 1.0 mL/min), isomer C (0.6 mg) as a whitesolid. LCMS (ESI, m/z): 532.30 [M+H]⁺, HNMR (400 MHz, DMSO-d₆) δ12.29(s, 1H), 8.51 (d, J=2.4 Hz, 1H), 8.16 (s, 1H), 7.89 (dd, J=9.1, 2.4 Hz,1H), 6.93 (d, J=9.2 Hz, 1H), 4.48 (q, J=7.5 Hz, 1H), 4.19 (t, J=6.3 Hz,1H), 3.72 (d, J=9.6 Hz, 3H), 3.65 (s, 2H), 3.54 (s, 5H), 3.19 (d, J=9.7Hz, 1H), 2.75-2.67 (m, 1H), 2.55 (m, 1H), 2.08 (d, J=6.9 Hz, 1H), 2.01(d, J=6.1 Hz, 1H), 1.89 (dd, J=13.1, 5.4 Hz, 2H), 1.64 (s, 3H),1.64-1.50 (m, 1H). tR=8.23 min CHIRALPAK ID-3, 0.46*10 cm; 3 um, MtBE(0.1% DEA):EtOH=80:20, 1.0 mL/min) and isomer D (1.6 mg) as a whitesolid. LCMS (ESI, m/z): 532.30 [M+H]⁺, HNMR (400 MHz, DMSO-d₆) δ12.37(s, 1H), 8.52 (d, J=2.3 Hz, 1H), 8.08 (s, 1H), 7.89 (dd, J=9.1, 2.4 Hz,1H), 6.93 (d, J=9.0 Hz, 1H), 4.71 (d, J=8.4 Hz, 1H), 4.20 (t, J=6.4 Hz,1H), 4.01 (t, J=7.1 Hz, 1H), 3.64-3.46 (m, 9H), 3.24 (s, 1H), 2.42 (dd,J=15.5, 6.7 Hz, 1H), 2.26 (dd, J=15.5, 6.1 Hz, 1H), 2.06-1.86 (m, 4H),1.63-1.44 (m, 4H). tR=4.27 min CHIRALPAK ID-3, 0.46*10 cm; 3 um, MtBE(0.1% DEA):EtOH=80:20, 1.0 mL/min)

Example 142:5-[(4aR,7aR)-1-acetyl-octahydro-1H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of Tert-Butyl(4aR,7aR)-6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate

A solution of tert-butyl(4aR,7aR)-octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (500 mg,2.21 mmol, 1 equiv), Cs₂CO₃ (1439.6 mg, 4.42 mmol, 2.0 equiv) and Int-A6(1086.3 mg, 3.31 mmol, 1.50 equiv) in MeCN (30 mL) was stirred for 2 hat 60° C., and then the resulting solution was diluted with 50 ml ofH₂O, extracted with 3×50 ml of EtOAc, the organic layer was washed with1×50 ml of brine, dried over anhydrous sodium sulfate and concentrated.Under vacuum, and then the residue was applied onto a silica gel columneluting with EtOAc/petroleum ether (16/84) to afford (85.96%) of thetitle compound as yellow oil. LCMS (ESI, m/z): δ 18.25 [M+H]⁺.

Step 2: Synthesis of5-[(4aR,7aR)-octahydro-1H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of tert-butyl(4aR,7aR)-6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate(500 mg, 0.96 mmol, 1.00 equiv) and TFA (2 mL) in DCM (10 mL) wasstirred for 2h at room temperature, and then the resulting solution wasconcentrated under vacuum to afford 200 mg of the title compound as acrude white solid. LCMS (ESI, m/z): 289.12[M+H]⁺.

Step 3: Synthesis of5-[(4aR,7aR)-1-acetyl-octahydro-1H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[(4aR,7aR)-octahydro-1H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(190 mg, 0.66 mmol, 1 equiv), Ac₂O (134.6 mg, 1.32 mmol, 2.00 equiv) andTEA (200.1 mg, 1.98 mmol, 3.0 equiv) in DCM (30 mL) was stirred for 2 hat room temperature, and then the resulting solution was diluted with 30mL of DCM, washed with 3×30 ml of H₂O, the organic layer was combinedand washed with 1×30 ml of brine, dried over anhydrous sodium sulfateand concentrated under vacuum, and then the residue was purified byPrep-HPLC yielding the title compound (86.4 mg, 39.69%) as a whitesolid. LCMS (ESI, m/z): 331.20 [M+H]⁺, ¹HNMR (DMSO-d₆, 300 MHz,) δ 7.87(s, 1H), 4.84-4.71 (m, 1H), 3.84 (d, J=5.4 Hz, 2H), 3.64 (d, J=9.9 Hz,2H), 3.53-3.20 (m, 2H), 2.28-2.19 (m, 1H), 2.03 (s, 3H), 1.78-1.35 (m,4H).

Example 143:5-[(4aS,7aS)-1-acetyl-octahydro-1H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of Tert-Butyl(4aS,7aS)-6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate

A solution of tert-butyl(4aS,7aS)-octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (500 mg,2.21 mmol, 1 equiv), Int-A6 (726.4 mg, 2.21 mmol, 1.00 equiv) and TEA(670.7 mg, 6.63 mmol, 3.00 equiv) in EtOH (10 mL) was stirred for 2 h at60° C., and then the resulting solution was concentrated under vacuum,and then the residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1:5) to afford 678 mg (59.17%) of the titlecompound as yellow oil. LCMS (ESI, m/z): 519.26[M+H]⁺.

Step 2: Synthesis of5-[(4aS,7aS)-octahydro-1H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of tert-butyl(4aS,7aS)-6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate(300 mg, 0.58 mmol, 1 equiv) in HCl/dioxane (9 mL, 4M) was stirred for2h at room temperature, and then the resulting solution was concentratedunder vacuum to afford 190 mg (63.33%) of the title compound as yellowoil. LCMS (ESI, m/z): 289.12 [M+H]+.

Step 3: Synthesis of5-[(4aS,7aS)-1-acetyl-octahydro-1H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[(4aS,7aS)-octahydro-1H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(729 mg, 2.53 mmol, 1 equiv), Ac₂O (516.3 mg, 5.06 mmol, 2.0 equiv) andTEA (767.7 mg, 7.59 mmol, 3.00 equiv) in DCM (10 mL, 0.12 mmol) wasstirred for 1.5h at room temperature, and then the resulting solutionwas concentrated under vacuum, and then the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN, afterconcentration, the residue was further purified by Prep-HPLC yieldingthe title compound (41.9 mg, 5.02%) as a white solid. LCMS (ESI, m/z):331.15 [M+H]⁺, ¹HNMR (DMSO-d₆, 300 MHz) δ 7.80 (s, 1H), 4.84-4.71 (m,1H), 3.82-3.20 (m, 6H), 2.32-2.19 (m, 1H), 2.03 (s, 3H), 1.76-1.27 (m,4H).

Example 144:6-[4-[2-([2-[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]ethyl]amino)acetyl]piperazin-1-yl]pyridine-3-carbonitrileand 6-[4-[2-([2-[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]ethyl]amino)acetyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of5-[1-(2-aminoethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[1-(2-azidoethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(370 mg, 0.77 mmol, 1 equiv), PPh₃ (242.3 mg, 0.92 mmol, 1.2 equiv) inTHF (15 mL) and H₂O (5 mL) was stirred for 1 h at 60° C. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column eluting with DCM/methanol (94/6) to afford 217 mg(62.00%) of the title compound as yellow oil. LCMS (ESI, m/z): 455.20[M+H]⁺

Step 2: Synthesis of6-[4-(2-chloroacetyl)piperazin-1-yl]pyridine-3-carbonitrile

To a solution of Int-A4 (1100 mg, 4.90 mmol, 1 equiv), TEA (1486.2 mg,14.69 mmol, 3 equiv) in DCM (10 mL), 2-chloroacetyl chloride (663.5 mg,5.87 mmol, 1.2 equiv) was added at 0° C. The resulting solution wasstirred for 1 h at 0° C. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (56/44) to afford 752 mg (58.03%) of the titlecompound as a yellow solid. LCMS (ESI, m/z): 265.08[M+H]⁺

Step 3: Synthesis of6-(4-[2-[(2-[2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]ethyl)amino]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of5-[1-(2-aminoethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(200 mg, 0.44 mmol, 1 equiv), TEA (89.0 mg, 0.88 mmol, 2 equiv),6-[4-(2-chloroacetyl)piperazin-1-yl]pyridine-3-carbonitrile (116.5 mg,0.44 mmol, 1 equiv) in EtOH (10 mL) was stirred for 25 h at 80° C. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column eluting with DCM/methanol (97/3). Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford 96 mg (31.95%) of thetitle compound as a yellow solid. LCMS (ESI, m/z): 683.30 [M+H]⁺

Step 4: Synthesis of6-[4-[2-([2-[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]ethyl]amino)acetyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[2-([2-[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]ethyl]amino)acetyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-(4-[2-[(2-[2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]ethyl)amino]acetyl]piperazin-1-yl)pyridine-3-carbonitrile(80 mg, 0.12 mmol, 1 equiv) in DCM (1 mL) and TFA (0.05 mL) was stirredfor 2 h at room temperature. The reaction was then quenched by theaddition of 5 mL of saturated sodium bicarbonate aqueous. The resultingsolution was extracted with 3×30 ml of DCM and the organic layerscombined. After concentration, the residue was purified by C18 reversephase chromatography eluting with H₂O/CH₃CN. Then the residue wasfurther purified by Prep-HPLC and Chiral-Prep-HPLC yielding (afterarbitrary assignment of stereochemistry) the title compounds,respectively, isomer A: (10.2 mg, 15.76%) as a white solid. LCMS (ESI,m/z): 553.22 [M+H]⁺, ¹H NMR (300 MHz, DMSO-d6) δ: 8.52 (d, J=2.4 Hz,1H), 8.26 (d, J=8.0 Hz, 1H), 7.89 (dd, J=9.0, 2.4 Hz, 1H), 7.45-7.27 (m,4H), 6.94 (d, J=9.1 Hz, 1H), 5.88 (d, J=5.7 Hz, 1H), 5.06 (d, J=14.9 Hz,1H), 4.51 (d, J=15.0 Hz, 1H), 3.73-3.62 (m, 8H), 3.53 (d, J=15.1 Hz,2H), 2.47 (d, J=7.0 Hz, 2H), 1.99 (d, J=14.4 Hz, 2H). tR=3.565 min(Chiralpak IG-3, 2*25 cm, 5 um, MtBE (0.1% TEA):MeOH=70:30, 1.0 mL/min)and isomer B: (10.0 mg, 15.45%) as a white solid. LCMS (ESI, m/z):553.22 [M+H]⁺, tR=4.753 min (Chiralpak IG-3, 2*25 cm, 5 um, MtBE (0.1%TEA):MeOH=70:30, 1.0 mL/min)

Example 145:6-[4-[(3R)-3-amino-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrile;formic acid and6-[4-[(3S)-3-amino-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrile;Formic Acid

Step 1: Synthesis of methyl(2E)-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-2-enoate

Under N2 (g) atmosphere, a solution of5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(2.0 g, 5.08 mmol, 1.00 equiv), Pd[(allyl)Cl]₂ (93.0 mg, 0.25 mmol, 0.05equiv), Rockphos (239 mg, 0.51 mmol, 0.10 equiv), Cs₂CO₃ (2.0 g, 6.14mmol, 1.30 equiv), methyl (2E)-4-bromobut-2-enoate (4.6 mg, 0.03 mmol,5.00 equiv) in toluene (5 mL) was stirred overnight at 80° C. in an oilbath. After concentration, the residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (27:73) to afford 800 mg (32%)of the title compound as yellow oil. LCMS (ESI, m/z): 492.21 [M+H]⁺

Step 2: Synthesis of methyl3-(benzylamino)-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoate

A solution of methyl(2E)-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]but-2-enoate(650 mg, 1.32 mmol, 1.00 equiv), 1-phenylmethanamine (700 mg, 6.53 mmol,5.00 equiv) in n-BuOH (15 mL) was stirred for 3 h at 100° C. in an oilbath. After concentration, the residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (61:39) to afford 630 mg (80%)of the title compound as a yellow oil. LCMS (ESI, m/z): 599.28 [M+H]⁺

Step 3: Synthesis of methyl3-[[(tert-butoxy)carbonyl]amino]-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoate

Under H₂, a solution of methyl3-(benzylamino)-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoate(600 mg, 1.00 mmol, 1.00 equiv), Palladium carbon (200 mg), (Boc)₂O (700mg, 3.21 mmol, 3.00 equiv) in methanol (30 mL) was stirred overnight at25° C. The solids were filtered out. After concentration, the residuewas applied onto a silica gel column eluting with EtOAc/petroleum ether(30:70) to afford 200 mg (33%) of the title compound as a light yellowoil. LCMS (ESI, m/z): 609.29 [M+H]⁺

Step 4: Synthesis of3-[[(tert-butoxy)carbonyl]amino]-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoicacid

A solution of methyl3-[[(tert-butoxy)carbonyl]amino]-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoate(190 mg, 0.31 mmol, 1.00 equiv), LiOH.H₂O (26 mg, 0.62 mmol, 2.00 equiv)in methanol (1 mL) and water (1 mL) was stirred for 6 h at 25° C. Theresulting mixture was concentrated under vacuum to afford 180 mg (97%)of the title compound d as a yellow oil. LCMS (ESI, m/z): 595.27 [M+H]⁺

Step 5: Synthesis of Tert-ButylN-[4-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-4-oxo-1-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butan-2-yl]carbamate

A solution of3-[[(tert-butoxy)carbonyl]amino]-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoicacid (180 mg, 0.30 mmol, 1.00 equiv), DIEA (40 mg, 0.31 mmol, 1.00equiv), HATU (115 mg, 0.30 mmol, 1.00 equiv), Int-A4 (59 mg, 0.31 mmol,1.00 equiv) in DMF (4 mL) was stirred for 1 overnight at 25° C. Afterconcentration, the residue was applied onto a silica gel column elutingwith EtOAc/petroleum ether (98:2) to afford 200 mg (86%) of the titlecompound as a white solid. LCMS (ESI, m/z): 766.37 [M+H]⁺

Step 6: Synthesis of6-[4-[(3R)-3-amino-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrile;Formic Acid and6-[4-[(3S)-3-amino-4-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrile;Formic Acid

A solution of tert-butylN-[4-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-4-oxo-1-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]butan-2-yl]carbamate(200 mg, 0.26 mmol, 1.00 equiv), a solution of TFA/DCM (12 mL) in DCM(10 mL) was stirred for 1 h at 25° C. The resulting mixture wasconcentrated under vacuum. Then adjusted its pH to 8 with NH₂CH₂CH₂OH.After concentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN and Chiral-Prep-HPLC yielding(after arbitrary assignment of stereochemistry) the title compounds,respectively, isomer A (10.5 mg 16%) as a white solid. LCMS (ESI, m/z):535.35 [M+H]⁺, ¹HNMR (Methanol-d₄, 300 MHz) δ: 8.55 (s, 1H), 8.47 (d,J=2.2 Hz, 1H), 8.25 (s, 1H), 7.81 (dd, J=9.1, 2.4 Hz, 1H), 6.92 (d,J=9.1 Hz, 1H), 4.70 (dr, 1H), 3.81-3.74 (m, 10H), 3.69-3.61 (m, 1H),3.59-3.40 (m, 4H), 2.68-2.67 (m, 1H), 2.58-2.55 (m, 1H), 2.30-2.28 (m,1H), 2.04-2.02 (m, 1H), 1.84-1.72 (m, 2H). tR=4.088 min (CHIRALPAK ID-3,0.46*10 cm; 3 um, MtBE (0.1% DEA):EtOH=70:30, 1.0 mL/min) and isomer B(20.9 mg 32%) as a white solid. LCMS (ESI, m/z): 535.30 [M+H]⁺, ¹HNMR(Methanol-d₄, 300 MHz) δ8.53 (s, 1H), 8.46 (d, J=1.8 Hz, 1H), 8.18 (s,1H), 7.82-7.78 (dd, J=9.1, 2.4 Hz, 1H), 6.93-6.90 (d, J=9.0 Hz, 1H),4.66 (dr, 1H), 3.84-3.60 (m, 11H), 3.58-3.40 (m, 3H), 3.45-3.38 (m, 1H),2.85-2.79 (m, 1H), 2.69-2.61 (m, 1H), 2.30-2.28 (m, 1H), 2.04-2.02 (m,1H), 1.84-1.72 (m, 2H). tR=6.124 min (CHIRALPAK ID-3, 0.46*10 cm; 3 um,MtBE (0.1% DEA):EtOH=70:30, 1.0 mL/min)

Example 146:6-[4-[3-([[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methyl]amino)propanoyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[3-([[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methyl]amino)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Synthesis of5-[1-(azidomethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

To a stirred solution of5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (900 mg, 2.04 mmol, 1.00equiv) in toluene (15 mL), DBU (0.8 mL) and DPPA (1 mL) were added. Theresulting solution was stirred for 10 h at 80° C. The resulting solutionwas diluted with 200 mL of EtOAc. The resulting mixture was washed with1×50 mL of NH₄Cl and 1×50 mL of NaHCO₃. The resulting mixture was washedwith 1×50 mL of Brine. The organic layer was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column with EtOAc/petroleum ether (1:4). This resulted in 700mg (crude) of the title compound as a white solid. LCMS (ESI, m/z):467.18 [M+H]⁺.

Step 2: Synthesis of5-[1-(aminomethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-[1-(azidomethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(700 mg, 1.50 mmol, 1.00 equiv) and Palladium carbon (100 mg) in EtOAc(50 mL) was stirred for 3 h at room temperature under hydrogen. Thesolids were filtered out. The resulting mixture was concentrated undervacuum. This resulted in 500 mg (crude) of the title compound as a whitesolid. LCMS (ESI, m/z): 441.19 [M+H]⁺

Step 3: Synthesis of Tert-Butyl3-[([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methyl)amino]propanoate

A solution of5-[1-(aminomethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(500 mg, 1.13 mmol, 1.00 equiv) and tert-butyl prop-2-enoate (0.5 mL) inethanol (10 mL) was stirred overnight at 100° C. The resulting mixturewas concentrated under vacuum. The residue was applied onto a silica gelcolumn with EtOAc/petroleum ether (1:1). This resulted in 200 mg (31%)of the title compound as yellow oil. LCMS (ESI, m/z): 569.28 [M+H]⁺.

Step 4: Synthesis of3-[([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methyl)amino]propanoicAcid

A solution of tert-butyl3-[([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methyl)amino]propanoate(110 mg, 0.19 mmol, 1.00 equiv) in hydrogen chloride/dioxane (10 mL) wasstirred overnight at room temperature. The resulting mixture wasconcentrated under vacuum. This resulted in 90 mg (crude) of the titlecompound as a solid. LCMS (ESI, m/z): 383.13 [M+H]⁺.

Step 5: Synthesis of3-[[(tert-butoxy)carbonyl]([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methyl)amino]propanoicAcid

A stirred solution of3-[([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methyl)amino]propanoicacid (90 mg, 0.24 mmol, 1.00 equiv) in THF (5 mL) and water (5 mL),sodium bicarbonate (50 mg, 0.60 mmol, 2.53 equiv) and Boc₂O (50 mg, 0.23mmol, 0.97 equiv) were added. The resulting solution was stirredovernight at room temperature. The pH value of the solution was adjustedto 2 with hydrogen chloride (1 M). The resulting solution was dilutedwith 100 mL of EtOAc. The resulting mixture was washed with 1×20 mL ofwater and 1×20 mL of Brine. The organic layer was dried over anhydroussodium sulfate and concentrated under vacuum. This resulted in 100 mg(crude) of the title compound as a solid. LCMS (ESI, m/z): 483.18[M+H]⁺.

Step 6: Synthesis of Tert-ButylN-[3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-3-oxopropyl]-N-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methyl)carbamate

To a stirred solution of3-[[(tert-butoxy)carbonyl]([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methyl)amino]propanoicacid (100 mg, 0.21 mmol, 1.00 equiv) in DMF (5 mL), Int-A4 (39 mg, 0.21mmol, 1.0 equiv), DIPEA (0.3 mL) and HATU (79 mg, 0.21 mmol, 1.0 equiv)were added. The resulting solution was stirred for 2 h at roomtemperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN. This resulted in 70mg (52%) of the title compound as a white solid. LCMS (ESI, m/z): 653.28[M+H]⁺.

Step 7: Synthesis of6-[4-[3-([[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]ethyl]amino)propanoyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[3-([[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methyl]amino)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

To a stirred solution of tert-butylN-[3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-3-oxopropyl]-N-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methyl)carbamate(70 mg, 0.11 mmol, 1.00 equiv) in DCM (5 mL), TFA (1.5 mL) was added.The resulting solution was stirred for 1 h at room temperature. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN. Then the residue was furtherpurified by Prep-HPLC and Chiral-Prep-HPLC yielding (after arbitraryassignment of stereochemistry) the title compounds, respectively, isomerA (3.1 mg, 25%) as a white solid. LCMS (ESI, m/z): 553.30 [M+H]⁺. ¹HNMR(Methanol-d₄, 400 MHz) δ 8.44 (d, J=2.3 Hz, 1H), 8.27 (s, 1H), 7.77 (dd,J=9.1, 2.4 Hz, 1H), 7.43 (dd, J=6.3, 3.4 Hz, 1H), 7.35 (d, J=3.0 Hz,3H), 6.87 (d, J=9.1 Hz, 1H), 5.79 (t, J=5.3 Hz, 1H), 5.23 (d, J=14.7 Hz,1H), 4.60 (d, J=15.1 Hz, 1H), 3.80-3.57 (m, 8H), 3.15 (dd, J=13.0, 4.8Hz, 1H), 2.99 (dd, J=13.0, 5.8 Hz, 1H), 2.94-2.83 (m, 2H), 2.55 (t,J=6.4 Hz, 2H). Rt=2.778 min (CHIRELPAK IF-3, 0.46*10 cm; 3 um, MtBE(0.1% DEA):EtOH=70:30, 1.0 mL/min) and isomer B (4.1 mg, 33%) as a whitesolid. LCMS (ESI, m/z): 553.30 [M+H]⁺. Rt=3.698 min (CHIRELPAK IF-3,0.46*10 cm; 3 um, MtBE (0.1% DEA):EtOH=70:30, 1.0 mL/min).

Example 147:5-[(2S)-2-[(2S,5S)-5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one,5-[(2S)-2-[(2S,5R)-5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one,5-[(2S)-2-[(2R,5S)-5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand5-[(2S)-2-[(2R,5R)-5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of5-[(2S)-2-(5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of2-[5-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]oxolan-2-yl]aceticacid (400 mg, 0.81 mmol, 1 equiv), Int-A3 (161 mg, 0.81 mmol, 1.00equiv), HATU (370.7 mg, 0.97 mmol, 1.20 equiv), DIEA (211.4 mg, 1.64mmol, 2.01 equiv) in DMF (4 mL) was stirred for 1 h at room temperature.After concentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford 450 mg (82.27%) of thetitle compound as yellow oil. LCMS (ESI, m/z): 672.26[M+H]⁺

Step 2: Synthesis of5-[(2S)-2-[(2S,5S)-5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one,5-[(2S)-2-[(2S,5R)-5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one,5-[(2S)-2-[(2R,5S)-5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand5-[(2S)-2-[(2R,5R)-5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[(2S)-2-(5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(450 mg, 0.67 mmol, 1 equiv), TFA (1 mL) in DCM (10 mL) was stirred for4 h at room temperature. After concentration, the residue was purifiedby C18 reverse phase chromatography eluting with H₂O/CH₃CN. Then theresidue was further purified by Prep-HPLC and Chiral-Prep-HPLC yielding(after arbitrary assignment of stereochemistry) the title compounds,respectively, isomer A (14.4 mg, 3.97%) as a white solid. LCMS (ESI,m/z): 542.95 [M+H]⁺, ¹HNMR (300 MHz, DMSO-d₆) δ: 12.23 (s, 1H), 8.46 (s,2H), 8.13-8.03 (m, 1H), 4.66 (s, 1H), 4.32-3.91 (m, 2H), 3.78-3.35 (m,9H), 3.28-3.18 (m, 1H), 2.72-2.60 (m, 1H), 2.41-2.38 (m, 1H), 2.16-1.85(m, 4H), 1.72-1.37 (m, 4H). tR=3.467 min (CHIRALPAK IG-3, 0.46*10 cm; 3um, MtBE (0.1% DEA):MeOH=80:20, 1.0 mL/min), isomer B (71.1 mg, 19.60%)as a white solid. LCMS (ESI, m/z): 542.95 [M+H]⁺, ¹HNMR (300 MHz,DMSO-d₆) δ: 12.23 (s, 1H), 8.44 (s, 2H), 8.05 (s, 1H), 4.50-4.39 (m,1H), 4.35-4.25 (m, 1H), 3.83 (q, J=7.5 Hz, 1H), 3.78-3.66 (m, 2H),3.63-3.40 (m, 7H), 3.20 (m, 1H), 2.67 (dd, J=14.7, 6.6 Hz, 1H), 2.40(dd, J=14.7, 6.1 Hz, 1H), 2.22-1.97 (m, 3H), 1.93-1.80 (m, 1H),1.72-1.44 (m, 4H). tR=4.847 min (CHIRALPAK IG-3, 0.46*10 cm; 3 um, MtBE(0.1% DEA):MeOH=80:20, 1.0 mL/min), isomer C (6.8 mg, 1.87%) as a whitesolid. LCMS (ESI, m/z): 542.95 [M+H]⁺, ¹HNMR (300 MHz, DMSO-d6) δ: 12.23(s, 1H), 8.44 (s, 2H), 8.05 (s, 1H), 4.46 (d, J=8.3 Hz, 1H), 4.30 (s,1H), 3.88-3.63 (m, 3H), 3.62-3.41 (m, 7H), 3.24-3.13 (m, 1H), 2.67 (dd,J=14.7, 6.6 Hz, 1H), 2.40 (dd, J=14.7, 6.3 Hz, 1H), 2.23-1.97 (m, 3H),1.93-1.80 (m, 1H), 1.71-1.47 (m, 4H). tR=5.783 min (CHIRALPAK IG-3,0.46*10 cm; 3 um, MtBE (0.1% DEA):MeOH=80:20, 1.0 mL/min) and isomer D(23.5 mg, 6.48%) as a white solid. LCMS (ESI, m/z): 542.95 [M+H]⁺, ¹HNMR(300 MHz, DMSO-d6) δ: 12.28 (s, 1H), 8.46 (s, 2H), 8.16 (s, 1H), 4.48(d, J=7.5 Hz, 1H), 4.20 (t, J=6.2 Hz, 1H), 3.77-3.66 (m, 5H), 3.61-3.45(m, 5H), 3.26-3.14 (m, 1H), 2.71 (dd, J=15.4, 6.1 Hz, 1H), 2.49-2.43 (m,1H), 2.13-1.96 (m, 2H), 1.93-1.80 (m, 2H), 1.72-1.50 (m, 4H). tR=6.854min (CHIRALPAK IG-3, 0.46*10 cm; 3 um, MtBE (0.1% DEA):MeOH=80:20, 1.0mL/min)

Example 148:5-[(2S)-2-[(2S,5S)-5-[2-[4-(5-chloropyridin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one,5-[(2S)-2-[(2R,5S)-5-[2-[4-(5-chloropyridin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one,5-[(2S)-2-[(2R,5R)-5-[2-[4-(5-chloropyridin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand5-[(2S)-2-[(2S,5R)-5-[2-[4-(5-chloropyridin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of2-[5-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]oxolan-2-yl]aceticAcid

A solution of 2-[5-[(2S)-pyrrolidin-2-yl]oxolan-2-yl]acetic acid (980mg, 4.92 mmol, 1.00 equiv), TEA (900 mg, 8.89 mmol, 3.00 equiv) andInt-A6 (600 mg, 1.82 mmol, 1.00 equiv) in methanol (20 mL) was stirredfor 3 h at 60° C., and then the resulting solution was concentratedunder vacuum, and then the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford 1.0 g (41%) of the titlecompound as yellow oil. LCMS (ESI, m/z): 492.21 [M+H]⁺

Step 2: Synthesis of5-[(2S)-2-(5-[2-[4-(5-chloropyridin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of2-[5-[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]oxolan-2-yl]aceticacid (400 mg, 0.81 mmol, 1.00 equiv), HATU (310 mg, 0.82 mmol, 1.00equiv), DIEA (421 mg, 3.26 mmol, 4.00 equiv) and Int-A5 (219 mg, 0.81mmol, 1.00 equiv) in DMF (6 mL) was stirred for 1 h at room temperature,and then the resulting solution was diluted with 10 mL of EtOAc, washedwith 3×8 mL of H₂O, the organic layer was combined, dried over anhydroussodium sulfate and concentrated under vacuum, and then the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN toafford 450 mg (82%) of the title compound as a light brown solid. LCMS(ESI, m/z): 671.27[M+H]⁺

Step 3: Synthesis of5-[(2S)-2-[(2S,5S)-5-[2-[4-(5-chloropyridin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand5-[(2S)-2-[(2R,5S)-5-[2-[4-(5-chloropyridin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand5-[(2S)-2-[(2R,5R)-5-[2-[4-(5-chloropyridin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand5-[(2S)-2-[(2S,5R)-5-[2-[4-(5-chloropyridin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[(2S)-2-(5-[2-[4-(5-chloropyridin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(450 mg, 0.67 mmol, 1.00 equiv) and TFA (1 mL) in DCM (5 mL) was stirredfor 1.5 h at room temperature, and then the resulting solution wasconcentrated under vacuum and then the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN, afterconcentration, the residue was further purified by Prep-HPLC andChiral-Prep-HPLC yielding (after arbitrary assignment ofstereochemistry) the title compounds, respectively, isomer A (7.7 mg2.10%) as a white solid. LCMS (ESI, m/z): 541.10[M+H]⁺, 1HNMR(Methanol-d₄, 400 MHz) δ 8.21 (s, 1H), 8.08 (d, J=2.4 Hz, 1H), 7.56 (dd,J=10.4, 2.8 Hz, 1H), 6.83 (dd, J=8.8, 0.8 Hz, 1H), 4.73 (t, J=7.7 Hz,1H), 4.34-4.31 (m, 1H), 4.12 (dd, J=8.6, 4.5 Hz, 1H), 3.81-3.52 (m, 9H),3.39 (dd, J=11.0, 5.9 Hz, 1H), 2.73 (dd, J=14.2, 7.9 Hz, 1H), 2.57 (dd,J=14.2, 4.4 Hz, 1H), 2.26-2.13 (m, 3H), 2.05-1.94 (m, 1H), 1.82-1.64 (m,4H). tR=4.786 min (CHIRALPAK IG-3, 0.46*10 cm; 3 um, MtBE (0.3%IPAmine):EtOH=80:20, 1.0 mL/min), isomer B (4.8 mg 1.32%) as a whitesolid. LCMS (ESI, m/z): 541.10 [M+H]⁺, ¹HNMR (Methanol-d4, 400 MHz) δ8.20 (s, 1H), 8.06 (d, J=2.7 Hz, 1H), 7.55 (dd, J=9.2, 2.8 Hz, 1H), 6.82(dd, J=9.2, 0.7 Hz, 1H), 4.78 (t, J=7.8 Hz, 1H), 4.34-4.31 (m, 1H), 4.12(dd, J=8.6, 4.5 Hz, 1H), 3.81-3.36 (m, 10H), 2.48 (dd, J=15.6, 7.6 Hz,1H), 2.39 (dd, J=15.2, 4.8 Hz, 1H), 2.27-2.20 (m, 1H), 2.10-2.03 (m,1H), 2.00-1.91 (m, 2H), 1.81-1.63 (m, 3H), 1.59-1.46 (m, 1H). tR=5.588min (CHIRALPAK IG-3, 0.46*10 cm; 3 um, MtBE (0.1% DEA):EtOH=80:20, 1.0mL/min), isomer C (67.1 mg 18.5%) as a white solid. LCMS (ESI, m/z):541.10 [M+H]⁺, ¹HNMR (Methanol-d4, 400 MHz) δ 8.13 (s, 1H), 8.06 (d,J=2.4 Hz, 1H), 7.55 (dd, J=9.2, 2.8 Hz, 1H), 6.79 (d, J=9.2 Hz, 1H),4.44-4.33 (m, 2H), 4.00-3.92 (m, 1H), 3.71-3.35 (m, 10H), 2.81 (dd,J=14.0, 8.0 Hz, 1H), 2.53 (dd, J=14.0, 4.4 Hz, 1H), 2.25-2.16 (m, 3H),1.98-1.91 (m, 1H), 1.82-1.58 (m, 4H). tR=2.182 min (Repaired IA-3,0.46*10 cm; 5 um, (Hex:DCM=3:1)(10 mmol NH3):MeOH=70:30, 1.0 mL/min) andisomer D (25.1 mg 6.90%) as a white solid. LCMS (ESI, m/z): 541.10[M+H]⁺: 1HNMR (Methanol-d4, 400 MHz) δ 8.27 (s, 1H), 8.09 (d, J=2.4,1H), 7.57 (dd, J=8.8, 2.4 Hz, 1H), 6.84 (d, J=8.8, 1H), 4.51-4.44 (m,1H), 4.36-4.25 (m, 1H), 3.82-3.32 (m, 11H), 2.88 (dd, J=14.8, 7.2 Hz,1H), 2.59 (dd, J=14.8, 5.2 Hz, 1H), 2.28-1.94 (m, 4H), 1.82-1.59 (m,4H). tR=2.755 min (Repaired IA-3, 0.46*10 cm; 5 um, (Hex:DCM=3:1)(10mmol NH3):MeOHOH=70:30, 1.0 mL/min).

Example 149:5-[(2S)-2-[(2S,5S)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one,5-[(2S)-2-[(2S,5R)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one,5-[(2S)-2-[(2R,5S)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand5-[(2S)-2-[(2R,5R)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Synthesis of Tert-Butyl(2S)-2-[5-(2-oxo-2-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]pyrrolidine-1-carboxylate

A solution of2-[5-[(2S)-1-[(tert-butoxy)carbonyl]pyrrolidin-2-yl]oxolan-2-yl]aceticacid (1.1 g, 3.67 mmol, 1.00 equiv), DEIA (1.42 g, 3.00 equiv), Int-A2(1.12 g, 3.67 mmol, 1.10 equiv), HATU (1.54 g, 4.05 mmol, 1.10 equiv) inDMF (15 mL) was stirred for 1 h at 25° C. After concentration, theresidue was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN to afford 1.08 g (57%) of the title compound as yellow oil.LCMS (ESI, m/z): 514.26 [M+H]⁺

Step 2: Synthesis of2-[5-[(2S)-pyrrolidin-2-yl]oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethan-1-oneHydrochloride

A solution of tert-butyl(2S)-2-[5-(2-oxo-2-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]pyrrolidine-1-carboxylate(1.08 g, 2.10 mmol, 1.00 equiv) in dioxane/HCl (50 mL, 4 M) was stirredfor 2 h at 25° C. The resulting solution was concentrated under vacuumto afford 900 mg (95%) of the title compound as yellow oil. LCMS (ESI,m/z): 414.20 [M+H]⁺

Step 3: Synthesis of5-[(2S)-2-[5-(2-oxo-2-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of2-[5-[(2S)-pyrrolidin-2-yl]oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethan-1-onehydrochloride (870 mg, 1.93 mmol, 1.00 equiv), TEA (637 mg, 6.30 mmol,3.00 equiv), Int-A6 (920 mg, 2.80 mmol, 1.00 equiv) in EtOH (20 mL) wasstirred for 2 h at 60° C. After concentration, the residue was appliedonto a silica gel column with EtOAc/petroleum ether (3/2) to afford 1.23g (90%) the title compound as yellow oil. LCMS (ESI, m/z): 706.29 [M+H]⁺

Step 4: Synthesis of5-[(2S)-2-[(2S,5S)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one,5-[(2S)-2-[(2S,5R)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one,5-[(2S)-2-[(2R,5S)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand5-[(2S)-2-[(2R,5R)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[(2S)-2-[5-(2-oxo-2-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1 g, 1.42 mmol, 1.00 equiv), TFA (4 mL) in DCM (20 mL) was stirred for2 h at 25° C. The pH value of the solution was adjusted to 8 withethanolamine. The solvent was concentrated under vacuum and the residuewas purified by C18 reverse phase chromatography eluting with H₂O/CH₃CN.Then the residue was further purified by Chiral-Prep-HPLC yielding(after arbitrary assignment of stereochemistry) the title compounds,respectively, isomer A (381.1 mg, 46.70%) as a white solid. LCMS (ESI,m/z): 576.21 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz) δ: 10.80 (s, 1H), 8.71(s, 2H), 8.05 (s, 1H), 4.45 (q, J=8.0 Hz, 1H), 4.30 (p, J=6.4 Hz, 1H),3.95-3.77 (m, 3H), 3.72-3.43 (m, 7H), 3.22-3.13 (m, 1H), 2.68 (dd,J=14.7, 6.8 Hz, 1H), 2.40 (dd, J=14.7, 6.0 Hz, 1H), 2.20-2.11 (m, 1H),2.04 (t, J=10.2 Hz, 2H), 1.86 (d, J=11.3 Hz, 1H), 1.71-1.62 (m, 4H).tR=4.347 min (CHIRALPAK ID-3, 0.46*10 cm; 3 um, MtBE (0.1%DEA):EtOH=80:20, 1.0 mL/min, isomer B (9.5 mg, 1.16%) as a white solid.LCMS (ESI, m/z): 576.21 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz) δ: 12.34 (s,1H), 8.73 (d, J=0.9 Hz, 2H), 8.10 (s, 1H), 4.65 (s, 1H), 4.17 (s, 1H),4.09 (t, J=6.4 Hz, 1H), 3.90-3.71 (m, 4H), 3.52 (d, J=31.6 Hz, 5H), 3.23(s, 1H), 2.66 (dd, J=15.0, 6.8 Hz, 1H), 2.43 (dd, J=14.9, 5.8 Hz, 1H),2.04 (d, J=14.8 Hz, 3H), 1.89 (s, 1H), 1.63-1.54 (m, 4H). tR=3.343 min(CHIRALPAK ID-3, 0.46*10 cm; 3 um, MtBE (0.1% DEA):EtOH=80:20, 1.0mL/min, isomer C (75.2 mg, 9.21%) as a white solid. LCMS (ESI, m/z):576.21 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz) δ 12.30 (s, 1H), 8.74 (d, J=0.9Hz, 2H), 8.16 (s, 1H), 4.48 (q, J=7.6 Hz, 1H), 4.20 (p, J=6.3 Hz, 1H),3.86 (t, J=5.2 Hz, 2H), 3.80 (d, J=4.8 Hz, 2H), 3.72 (q, J=7.1 Hz, 1H),3.54 (q, J=6.1, 5.7 Hz, 5H), 3.20 (dd, J=10.5, 6.6 Hz, 1H), 2.72 (dd,J=15.4, 6.2 Hz, 1H), 2.50-2.42 (m, 1H), 2.11-1.97 (m, 2H), 1.90 (ddt,J=17.2, 10.5, 4.7 Hz, 2H), 1.63-1.54 (m, 4H). 1.60 (ddt, J=34.2, 13.3,6.5 Hz, 4H). tR=8.697 min (CHIRALPAK ID-3, 0.46*10 cm; 3 um, MtBE (0.1%DEA):EtOH=80:20, 1.0 mL/min and isomer D (11.2 mg, 1.37%) as a whitesolid. LCMS (ESI, m/z): 576.21 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz) δ:12.25 (s, 1H), 8.71 (d, J=0.9 Hz, 2H), 8.05 (s, 1H), 4.46 (q, J=8.0 Hz,1H), 4.30 (q, J=6.6 Hz, 1H), 3.91-3.77 (m, 3H), 3.70-3.39 (m, 7H), 3.18(t, J=8.8 Hz, 1H), 2.68 (dd, J=14.7, 6.8 Hz, 1H), 2.40 (dd, J=14.6, 6.0Hz, 1H), 2.15 (d, J=10.1 Hz, 1H), 2.04 (dd, J=12.4, 7.7 Hz, 2H), 1.86(d, J=10.7 Hz, 1H), 1.71-1.62 (m, 4H). tR=5.195 min (CHIRALPAK ID-3,0.46*10 cm; 3 um, MtBE (0.1% DEA):EtOH=80:20, 1.0 mL/min.

Example 150:5-[5-(Piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1:5-(5-Hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of Int-A6 (2.8 g, 8.52 mmol, 1.00 equiv),2,3-dihydro-1H-isoindol-5-ol hydrobromide (4.27 g, 19.76 mmol, 1.00equiv), and TEA (10 mL) in ethanol (40 mL) was stirred for 1 h at 60° C.The resulting solution was extracted with 2×100 mL of EtOAc and theorganic layers combined and concentrated under reduced pressure toafford 4.5 g of the title compound as a yellow oil. LCMS: [M+H]⁺ 428.23.

Step 2: tert-Butyl4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate

A solution of5-(5-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(4.5 g, 10.53 mmol, 1.00 equiv), tert-butyl4-iodopiperidine-1-carboxylate (20 g, 64.28 mmol, 8.00 equiv), potassiumcarbonate (15 g, 108.53 mmol, 10.00 equiv), and DMF (50 mL) was stirredfor 2 days at 80° C. The resulting solution was extracted with 2×200 mLof EtOAc and the organic layers combined and concentrated under reducedpressure. The residue was applied onto a silica gel column eluting withEtOAc/petroleum ether to afford the title compound (2 g, 31%) as ayellow oil. LCMS: [M+H]⁺ 611.15.

Step 3:5-[5-(Piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of tert-butyl4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate(150 mg, 0.25 mmol, 1.00 equiv) in HCl/dioxane (5 mL) was stirredovernight at 45° C. The resulting mixture was concentrated under reducedpressure and the crude product was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford the title compound as awhite solid LCMS: [M+H]⁺ 381.28. ¹H NMR (400 MHz, Methanol-d₄) δ 8.05(s, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.02-6.91 (m, 2H), 5.00 (d, J=10.6 Hz,4H), 4.61-4.48 (m, 1H), 3.21-3.10 (m, 2H), 2.89-2.78 (m, 2H), 2.11-2.08(m, 2H), 1.82-1.69 (m, 2H).

Further example compounds of the invention prepared by the methodsdescribed herein are provided in Table E1

TABLE E1 MS Example # Structure (M + H)⁺ 151

247.90 4-Chloro-5-(isoindolin-2-yl)pyridazin-3(2H)-one 152

249.05 4-Chloro-5-(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)pyridazin-3(2H)-one 153

277.65 4-Chloro-5-(4-methoxyisoindolin-2-yl) pyridazin-3(2H)-one 154

249.10 4-Chloro-5-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)pyridazin-3(2H)-one 155

278.05 4-Chloro-5-(5-methoxyisoindolin-2-yl) pyridazin-3(2H)-one 156

322.35 4-Chloro-5-(5-(2-methoxyethoxy)isoindolin-2-yl)pyridazin-3(2H)-one 157

308.30 4-Chloro-5-(5-(2-hydroxyethoxy)isoindolin-2-yl)pyridazin-3(2H)-one 158

347.35 4-Chloro-5-(5-(piperidin-4-yloxy)isoindolin-2-yl)pyridazin-3(2H)-one 159

228.20 5-(Isoindolin-2-yl)-4-methylpyridazin- 3(2H)-one 160

282.05 5-(Isoindolin-2-yl)-4-(trifluoromethyl) pyridazin-3(2H)-one 161

308.00 4-Chloro-5-(4-(2-hydroxyethoxy)isoindolin-2-yl)pyridazin-3(2H)-one 162

322.20 4-Chloro-5-(4-(2-methoxyethoxy)isoindolin-2-yl)pyridazin-3(2H)-one 163

307.20 5-(4-(2-Aminoethoxy)isoindolin-2-yl-) 4-chloropyridazin-3(2H)-one164

312.10 5-(4-Methoxyisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 165

347.40 4-Chloro-5-(4-(piperidin-4-yloxy)isoindolin-2-yl)pyridazin-3(2H)-one 166

335.35 4-Chloro-5-(4-(2-(dimethylamino)ethoxy)isoindolin-2-yl)pyridazin-3(2H)-one 167

258.20 5-(4-Methoxyisoindolin-2-yl)-4-methylpyridazin- 3(2H)-one 168

354.00 4-Bromo-5-(4-(2-hydroxyethoxy)isoindolin-2-yl)pyridazin-3(2H)-one 169

300.1 5-(5-Fluoroisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 170

381.15 5-(4-(Piperidin-4-yloxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 171

288.20 5-(4-(2-Hydroxyethoxy)isoindolin-2-yl)-4-methylpyridazin-3(2H)-one 172

391.00 4-Bromo-5-(4-(piperidin-4-yloxy)isoindolin-2-yl)pyridazin-3(2H)-one 173

258.20 5-(5-Methoxyisoindolin-2-yl)-4-methylpyridazin- 3(2H)-one 174

312.05 5-(5-Methoxyisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 175

327.25 4-Methyl-5-(4-(piperidin-4-yloxy)isoindolin-2-yl)pyridazin-3(2H)-one 176

299.20 5-(4-(2-Hydroxyethoxy)isoindolin-2-yl)-3-oxo-2,3-dihydropyridazine-4-carbonitrile 177

342.20 5-(5-(2-Hydroxyethoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 178

325.25 5-(4-(Dimethylamino)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 179

339.00 N-(2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-4-yl)acetamide 180

300.0 5-(4-Fluoroisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 181

342.00 5-(4-(2-Hydroxyethoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 182

338.40 3-Oxo-5-(4-(piperidin-4-yloxy)isoindolin-2-yl)-2,3-dihydropyridazine-4-carbonitrile formic acid 183

353.40 4-Cyclopropyl-5-(4-(piperidin-4-yloxy)isoindolin-2-yl)pyridazin-3(2H)-one formic acid 184

304.20 5-(4-(2-Hydroxyethoxy)isoindolin-2-yl)-4-methoxypyridazin-3(2H)-one 185

302.05 4-Ethyl-5-(4-(2-hydroxyethoxy)isoindolin-2-yl)pyridazin-3(2H)-one 186

314.40 4-Cyclopropyl-5-(4-(2-hydroxyethoxy)isoindolin-2-yl)pyridazin-3(2H)-one 187

327.40 4-Methyl-5-(5-(piperidin-4-yloxy)isoindolin-2-yl)pyridazin-3(2H)-one 188

288.20 5-(5-(2-Hydroxyethoxy)isoindolin-2-yl)-4-methylpyridazin-3(2H)-one 189

260.10 5-(Isoindolin-2-yl)-4-(methylthio)pyridazin-3(2H)- one 190

381.40 5-(5-(Piperidin-4-yloxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 191

278.15 4-Chloro-5-(1-(hydroxymethyl)isoindolin-2- yl)pyridazin-3(2H)-one192

326.20 5-(4-Ethoxyisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 193

340.20 5-(4-Isopropoxyisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 194

382.20 5-(4-((Tetrahydro-2H-pyran-4-yl)oxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 195

376.15 5-(4-(Pyrimidin-4-yloxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 196

389.15 5-(4-(Pyridin-4-ylmethoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 197

389.20 5-(4-(Pyridin-3-ylmethoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 198

389.15 5-(4-(Pyridin-2-ylmethoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 199

396.20 5-(4-((Tetrahydro-2H-pyran-3-yl)methoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 200

382.10 5-(4-((Tetrahydrofuran-3-yl)methoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 201

382.05 5-(4-((Tetrahydrofuran-2-yl)methoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 202

382.15 5-(4-((2-Oxotetrahydrofuran-3-yl)oxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 203

367.95 5-(4-((Tetrahydrofuran-3-yl)oxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 204

355.10 2-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-4-yl)oxy)acetamide 205

297.10 5-(4-Aminoisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 206

307.10 2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindoline-4-carbonitrile 207

292.05 4-Chloro-5-(1-(methoxymethyl)isoindolin-2- yl)pyridazin-3(2H)-one208

262.00 4-Chloro-5-(1-methylisoindolin-2-yl)pyridazin-3(2H)- one 209

341.15 5-(4-(2-Aminoethoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 210

395.15 5-(4-((1-Methylpiperidin-4-yl)oxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 211

383.15 N-(2-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-4- yl)oxy)ethyl)acetamide 212

369.20 5-(4-(2-(Dimethylamino)ethoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 213

409.15 5-(4-(2-(Piperidin-1-yl)ethoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 214

411.45 5-(4-(2-Morpholinoethoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 215

311.15 5-(4-(Methylamino)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 216

396.20 5-(4-((Tetrahydro-2H-pyran-2-yl)methoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 217

355.15 5-(4-(2-(Methylamino)ethoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 218

367.15 5-(5-(Pyrrolidin-3-yloxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 219

298.15 5-(5-Hydroxyisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 220

376.2 4-Chloro-5-(4-(2-(piperazin-1-yl)ethoxy)isoindolin-2-yl)pyridazin-3(2H)-one 221

311.15 5-(4-(Aminomethyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  222^(#)

382.10 (S)-5-(4-((Tetrahydrofuran-2-yl)methoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  223^(#)

382.10 (R)-5-(4-((Tetrahydrofuran-2-yl)methoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 224

397.15 N-Methyl-N-(2-((2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-4- yl)oxy)ethyl)acetamide 225

422.95 5-(4-((1-Acetylpiperidin-4-yl)oxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 226

424.15 5-(4-(2-(4-Methylpiperazin-1-yl)ethoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 227

410.40 5-(4-(2-(Piperazin-1-yl)ethoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 228

452.15 5-(4-(2-(4-Acetylpiperazin-1-yl)ethoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 229

356.1 5-(5-(2- Methoxyethoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 230

418.2 5-(4-(2-(4-Acetylpiperazin-1-yl)ethoxy)isoindolin-2-yl)-4-chloropyridazin-3(2H)-one 231

277.10 5-(1-(Aminomethyl)isoindolin-2-yl)-4- chloropyridazin-3(2H)-one232

375.20 5-(4-(pyridin-4-yloxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetic acid 233

375.20 5-(4-(Pyridin-3-yloxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 234

330.05 5-(5-Fluoro-6-methoxyisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 235

311.95 5-(1-(Hydroxymethyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 236

282.9 5-(5,7-Dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 237

297.25 5-(4-Hydroxyisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 238

381.40 5-(5-((1-Methylpyrrolidin-3-yl)oxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 239

326.10 5-(1-(Methoxymethyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 240

377.2 4-Chloro-5-(4-(2-morpholinoethoxy)isoindolin-2-yl)pyridazin-3(2H)-one 241

349.1 N-(2-((2-(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)isoindolin-4-yl)oxy)ethyl)acetamide 242

333.1 4-Chloro-5-(4-(pyrrolidin-3-yloxy)isoindolin-2-yl)pyridazin-3(2H)-one 243

316.15 5-(4-(2-Hydroxyethoxy)isoindolin-2-yl)-4-isopropylpyridazin-3(2H)-one 244

381.15 5-(5-(Piperidin-3-yloxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 245

360.05 5-(5-Fluoro-6-(2-hydroxyethoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  246^(#)

312.05 (R)-5-(1-(Hydroxymethyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  247^(#)

312.05 (S)-5-(1-(Hydroxymethyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 248

355.20 4-Isopropyl-5-(4-(piperidin-4-yloxy)isoindolin-2-yl)pyridazin-3(2H)-one 249

296.05 5-(1-Methylisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  250^(#)

296.05 (S)-5-(1-Methylisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  251^(#)

296.05 (R)-5-(1-Methylisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 252

403.10 5-(4-(1-(Pyridin-4-yl)ethoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 253

367.15 5-(4-Morpholinoisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 254

381.13 5-(4-(((Tetrahydrofuran-2- yl)methyl)amino)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 255

390.2 4-Chloro-5-(4-(2-(4-methylpiperazin-1-yl)ethoxy)isoindolin-2-yl)pyridazin-3(2H)-one 256

375.1 4-Chloro-5-(4-(2-(piperidin-1-yl)ethoxy)isoindolin-2-yl)pyridazin-3(2H)-one 257

361.1 4-Chloro-5-(4-((1-methylpiperidin-4-yl)oxy)isoindolin-2-yl)pyridazin-3(2H)-one 258

389.1 5-(4-((1-Acetylpiperidin-4-yl)oxy)isoindolin-2-yl)-4-chloropyridazin-3(2H)-one 259

347.1 4-Chloro-5-(4-((1-methylpyrrolidin-3-yl)oxy)isoindolin-2-yl)pyridazin-3(2H)-one 260

326.25 5-(4-(Methoxymethyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 261

312.05 5-(4-(Hydroxymethyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 262

325.10 5-(4-((Methylamino)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 263

395.10 5-(5-((1-Methylpiperidin-4-yl)oxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 264

353.15 N-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1- yl)methyl)acetamide 265

315.85 5-(4-Chloroisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 266

388.15 5-(4-((Pyridin-4-ylmethyl)amino)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 267

330.05 5-(4-Fluoro-7-methoxyisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 268

382.20 5-(4-((Tetrahydro-2H-pyran-3-yl)oxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 269

325.15 2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindoline-4-carboxamide 270

395.15 5-(4-(Methyl((tetrahydrofuran-2-yl)methyl)amino)isoindolin-2-yl)-4- (trifluoromethyl)pyridazin-3(2H)-one271

402.10 5-(4-((1-(Pyridin-4-yl)ethyl)amino)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 272

341.20 4-Ethyl-5-(4-(piperidin-4-yloxy)isoindolin-2-yl)pyridazin-3(2H)-one 273

330.10 5-(4-Fluoro-6-methoxyisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 274

330.10 5-(6-Fluoro-4-methoxyisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 275

311.10 5-(1-(Aminomethyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 276

367.10 N-Methyl-N-((2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1- yl)methyl)acetamide 277

353.10 N,N-Dimethyl-2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindoline-4-carboxamide 278

326.15 5-(4-(1-Hydroxyethyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 279

399.25 5-(5-Fluoro-6-(piperidin-4-yloxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 280

283.00 5-(1,3-Dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 281

408.30 5-(4-(4-(Dimethylamino)piperidin-1-yl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 282

395.15 5-(4-(Methyl(tetrahydro-2H-pyran-4- yl)amino)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 283

360.15 5-(4-Fluoro-7-(2-hydroxyethoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 284

351.15 5-(4-(Pyrrolidin-1-yl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 285

394.20 5-(4-(3-(Dimethylamino)pyrrolidin-1-yl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 286

429.15 5-(4-Fluoro-7-(2-morpholinoethoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 287

355.15 4-Isopropyl-5-(5-(piperidin-3-yloxy)isoindolin-2-yl)pyridazin-3(2H)-one  288^(#)

381.20 (R)-5-(5-(Piperidin-3-yloxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  289^(#)

381.20 (S)-5-(5-(Piperidin-3-yloxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 290

381.15 5-(4-((Tetrahydro-2H-pyran-4-yl)amino)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 291

399.14 5-(4-Fluoro-7-(piperidin-4-yloxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  292^(#)

355.20 (R)-4-Isopropyl-5-(5-(piperidin-3-yloxy)isoindolin-2-yl)pyridazin-3(2H)-one  293^(#)

355.20 (S)-4-Isopropyl-5-(5-(piperidin-3-yloxy)isoindolin-2-yl)pyridazin-3(2H)-one 294

407.90 5-(4-(4-Acetylpiperazin-1-yl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 295

365.95 5-(4-(Piperazin-1-yl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 296

379.90 5-(4-(4-Aminopiperidin-1-yl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 297

380.10 5-(4-(Piperidin-4-ylamino)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  298^(#)

394.10 (R)-5-(4-(Methyl((tetrahydrofuran-2-yl)methyl)amino)isoindolin-2-yl)-4- (trifluoromethyl)pyridazin-3(2H)-one 299^(#)

394.10 (S)-5-(4-(Methyl((tetrahydrofuran-2-yl)methyl)amino)isoindolin-2-yl)-4- (trifluoromethyl)pyridazin-3(2H)-one300

436.25 5-(4-((2,2,6,6-Tetramethylpiperidin-4-yl)amino)isoindolin-2-yl)-4- (trifluoromethyl)pyridazin-3(2H)-one 301

380.15 5-(4-(3-Aminopiperidin-1-yl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 302

394.20 5-(4-(Methyl(piperidin-4-yl)amino)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 303

313.10 5-(2-Methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 304

317.05 5-(2-Chloro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 305

367.10 5-(4-(3-Hydroxypyrrolidin-1-yl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 2,2,2- trifluoroacetic acid 306

365.90 5-(4-(3-Aminopyrrolidin-1-yl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 307

380.85 5-(4-((Tetrahydro-2H-pyran-3-yl)amino)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 308

326.00 5-(4-Methoxy-1-methylisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 309

326.00 5-(7-Methoxy-1-methylisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 310

310.10 5-(1-Ethylisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 311

356.80 5-(2-(2-Methoxyethoxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-(trifluoromethyl)pyridazin-3(2H)- one 312

343.10 5-(2-(2-Hydroxyethoxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-(trifluoromethyl)pyridazin-3(2H)- one 313

390.05 5-(2-(Pyridin-3-ylmethoxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4- (trifluoromethyl)pyridazin-3(2H)-one 314

379.85 5-(4-(4-Methylpiperazin-1-yl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 315

344.10 5-(5-Fluoro-6-methoxy-1-methylisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 316

412.10 5-(2-(2-Morpholinoethoxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4- (trifluoromethyl)pyridazin-3(2H)-one 317

341.85 5-(2-(2-Aminoethoxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-(trifluoromethyl)pyridazin-3(2H)- one formic acid 318

356.10 5-(2-(2-(Methylamino)ethoxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4- (trifluoromethyl)pyridazin-3(2H)-one 319

369.80 5-(2-(2-(Dimethylamino)ethoxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4- (trifluoromethyl)pyridazin-3(2H)-one 320

297.05 5-(2-Methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 321

390.05 5-(2-(Pyridin-4-ylmethoxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4- (trifluoromethyl)pyridazin-3(2H)-one 322

311.15 5-(5-(Aminomethyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 323

359.85 5-(4-Fluoro-6-(2-hydroxyethoxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 324

381.85 5-(2-(Piperidin-4-yloxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-(trifluoromethyl)pyridazin-3(2H)- one 325

412.10 5-(3-(2-Morpholinoethoxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4- (trifluoromethyl)pyridazin-3(2H)-one 326

313.05 5-(3-Methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 327

329.20 5-(5-(Aminomethyl)-6-fluoroisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 328

416.15 5-(4-((Methyl(pyridin-4-ylmethyl)amino)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 329

402.15 5-(4-(((Pyridin-4-ylmethyl)amino)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 330

321.05 2-(2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)acetonitrile 331

387.10 5-(6-(2-(Dimethylamino)ethoxy)-4-fluoroisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 332

326.20 5-(6-Methoxy-1-methylisoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 333

424.10 5-(2-((1-Acetylpiperidin-4-yl)oxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4- (trifluoromethyl)pyridazin-3(2H)-one 334

342.10 5-(3-(2-Aminoethoxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-(trifluoromethyl)pyridazin-3(2H)- one 335

370.10 5-(3-(2-(Dimethylamino)ethoxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4- (trifluoromethyl)pyridazin-3(2H)-one 336

390.05 5-(3-(Pyridin-3-ylmethoxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4- (trifluoromethyl)pyridazin-3(2H)-one 337

313.05 5-(4-Methoxy-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 338

424.15 5-(4-((1-Acetylpiperidin-4-yl)oxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4- (trifluoromethyl)pyridazin-3(2H)-one 339

388.10 5-(4-((Pyridin-4-ylamino)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 340

602.05 6-(4-(3-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)benzoyl)piperazin-1-yl)nicotinonitrile 341

577.15 5-(1-((3-(4-(Pyridin-2-yl)piperazine-1-carbonyl)phenoxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 342

432.00 3-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1- yl)methoxy)benzoic acid 343

614.85 6-(4-(3-(Methyl((2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1- yl)methyl)amino)benzoyl)piperazin-1-yl)nicotinonitrile 344

590.30 5-(1-((Methyl(3-(4-(pyridin-2-yl)piperazine-1-carbonyl)phenyl)amino)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 345

445.05 3-(Methyl((2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1- yl)methyl)amino)benzoic acid 346

313.10 5-(4-Methoxy-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 347

561.10 5-(4-((1-(2,2-Diphenylethyl)piperidin-4-yl)oxy)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin- 3(2H)-one 348

601.10 6-(4-(3-(((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1- yl)methyl)amino)benzoyl)piperazin-1-yl)nicotinonitrile  349*

557.10 (S)-5-(1-((3-(4-(Pyridin-2-yl)piperazine-1-carbonyl)phenoxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  350*

557.10 (R)-5-(1-((3-(4-(Pyridin-2-yl)piperazine-1-carbonyl)phenoxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 351

576.25 5-(1-(((3-(4-(Pyridin-2-yl)piperazine-1-carbonyl)phenyl)amino)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 352

603.10 6-(4-(5-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)nicotinoyl)piperazin-1-yl)nicotinonitrile  353*

603.10 (S)-6-(4-(5-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)nicotinoyl)piperazin-1-yl)nicotinonitrile  354*

603.10 (R)-6-(4-(5-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)nicotinoyl)piperazin-1-yl)nicotinonitrile 355

603.10 6-(4-(4-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)picolinoyl)piperazin-1-yl)nicotinonitrile  356*

603.10 (R)-6-(4-(4-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)picolinoyl)piperazin-1-yl)nicotinonitrile  357*

603.10 (S)-6-(4-(4-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)picolinoyl)piperazin-1-yl)nicotinonitrile 358

602.10 2-(4-(3-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)benzoyl)piperazin-1-yl)nicotinonitrile  359*

602.10 (S)-2-(4-(3-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)benzoyl)piperazin-1-yl)nicotinonitrile  360*

602.10 (R)-2-(4-(3-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)benzoyl)piperazin-1-yl)nicotinonitrile 361

603.00 2-(4-(3-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)benzoyl)piperazin-1-yl)pyrimidine-5- carbonitrile 362

514.10 5-(1-((3-(4-Methylpiperazine-1-carbonyl)phenoxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 363

500.10 5-(1-((3-(Piperazine-1-carbonyl)phenoxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  364*

603.00 (R)-2-(4-(3-((2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)benzoyl)piperazin-1-yl)pyrimidine-5- carbonitrile  365*

603.00 (S)-2-(4-(3-((2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)benzoyl)piperazin-1-yl)pyrimidine-5- carbonitrile 366

603.20 5-(4-(3-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)benzoyl)piperazin-1-yl)pyrazine-2- carbonitrile 367

606.00 4-(Trifluoromethyl)-5-(1-((3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)phenoxy)methyl)isoindolin-2-yl)pyridazin- 3(2H)-one 368

645.20 4-(Trifluoromethyl)-5-(1-((3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)phenoxy)methyl)isoindolin-2-yl)pyridazin- 3(2H)-one  369*

603.20 (R)-5-(4-(3-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)benzoyl)piperazin-1-yl)pyrazine-2- carbonitrile  370*

603.20 (S)-5-(4-(3-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)benzoyl)piperazin-1-yl)pyrazine-2- carbonitrile 371

602.20 6-(4-(4-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)benzoyl)piperazin-1-yl)nicotinonitrile  372*

606.00 (R)-4-(Trifluoromethyl)-5-(1-((3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)phenoxy)methyl)isoindolin-2-yl)pyridazin- 3(2H)-one  373*

606.00 (S)-4-(Trifluoromethyl)-5-(1-((3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)phenoxy)methyl)isoindolin-2-yl)pyridazin- 3(2H)-one 374

646.15 4-(Trifluoromethyl)-5-(1-(((5-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)pyridin-3-yl)oxy)methyl)isoindolin-2- yl)pyridazin-3(2H)-one375

596.10 5-(1-(((5-(4-(5-Fluoropyridin-2-yl)piperazine-1-carbonyl)pyridin-3-yl)oxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 376

612.05 5-(1-(((5-(4-(5-Chloropyridin-2-yl)piperazine-1-carbonyl)pyridin-3-yl)oxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 377

646.25 4-(Trifluoromethyl)-5-(1-((3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenoxy)methyl)isoindolin-2-yl)pyridazin- 3(2H)-one 378

647.05 4-(Trifluoromethyl)-5-(1-(((5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyridin-3-yl)oxy)methyl)isoindolin-2- yl)pyridazin-3(2H)-one379

604.20 2-(4-(5-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)nicotinoyl)piperazin-1-yl)pyrimidine-5- carbonitrile 380

604.05 2-(4-(4-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)picolinoyl)piperazin-1-yl)pyrimidine-5- carbonitrile 381

603.10 6-(4-(2-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)isonicotinoyl)piperazin-1- yl)nicotinonitrile 382

604.55 6-(4-(6-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)pyrazine-2-carbonyl)piperazin-1- yl)nicotinonitrile 383

604.20 6-(4-(2-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)pyrimidine-4-carbonyl)piperazin-1- yl)nicotinonitrile  384*

646.05 (S)-4-(Trifluoromethyl)-5-(1-(((5-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)pyridin-3-yl)oxy)methyl)isoindolin-2- yl)pyridazin-3(2H)-one 385*

646.05 (R)-4-(Trifluoromethyl)-5-(1-(((5-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)pyridin-3-yl)oxy)methyl)isoindolin-2- yl)pyridazin-3(2H)-one 386*

596.50 (S)-5-(1-(((5-(4-(5-Fluoropyridin-2-yl)piperazine-1-carbonyl)pyridin-3-yl)oxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  387*

596.50 (R)-5-(1-(((5-(4-(5-Fluoropyridin-2-yl)piperazine-1-carbonyl)pyridin-3-yl)oxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  388*

612.05 (S)-5-(1-(((5-(4-(5-Chloropyridin-2-yl)piperazine-1-carbonyl)pyridin-3-yl)oxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  389*

612.05 (R)-5-(1-(((5-(4-(5-Chloropyridin-2-yl)piperazine-1-carbonyl)pyridin-3-yl)oxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  390*

646.25 (S)-4-(Trifluoromethyl)-5-(1-((3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenoxy)methyl)isoindolin-2-yl)pyridazin- 3(2H)-one  391*

646.25 (R)-4-(Trifluoromethyl)-5-(1-((3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenoxy)methyl)isoindolin-2-yl)pyridazin- 3(2H)-one  392*

647.05 (S)-4-(Trifluoromethyl)-5-(1-(((5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyridin-3-yl)oxy)methyl)isoindolin-2- yl)pyridazin-3(2H)-one 393*

647.05 (R)-4-(Trifluoromethyl)-5-(1-(((5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyridin-3-yl)oxy)methyl)isoindolin-2- yl)pyridazin-3(2H)-one394

576.20 3-((5-Cyanopyridin-2-yl)amino)-N-(3-((2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)phenyl)propanamide  395*

604.20 (S)-2-(4-(5-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)nicotinoyl)piperazin-1-yl)pyrimidine-5- carbonitrile  396*

604.20 (R)-2-(4-(5-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)nicotinoyl)piperazin-1-yl)pyrimidine-5- carbonitrile 397

603.05 6-(4-(3-((6-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)methoxy)benzoyl)piperazin-1- yl)nicotinonitrile 398

538.10 5-(1-((3-(5,6,7,8-Tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)phenoxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 399

538.10 5-(1-((3-(4,5,6,7-Tetrahydro-[1,2,3]triazolo[1,5-a]pyrazine-5-carbonyl)phenoxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 400

602.60 6-(4-(4-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-4-yl)methoxy)benzoylpiperazin-1-yl)nicotinonitrile 401

616.60 6-(4-(3-(2-(2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-4-yl)ethoxy)benzoyl)pierazin-1-yl)nicotinonitrile 402

616.20 6-(4-(4-(2-(2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-4-yl)ethoxy)benzoyl)piperazin-1-yl)nicotinonitrile 403

591.25 5-(1-((3-(4-(5-Methylpyridin-2-yl)piperazine-1-carbonyl)phenoxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 404

537.10 5-(1-((3-(4,5,6,7-Tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)phenoxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 405

542.10 5-(1-((3-(4-Acetylpiperazine-1-carbonyl)phenoxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  406*

542.10 (R)-5-(1-((3-(4-Acetylpiperazine-1-carbonyl)phenoxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  407*

542.10 (S)-5-(1-((3-(4-Acetylpiperazine-1-carbonyl)phenoxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 408

568.20 6-(4-(4-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)butanoyl)piperazin-1-yl)nicotinonitrile  409*

568.20 (R)-6-(4-(4-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)butanoyl)piperazin-1-yl)nicotinonitrile  410*

568.20 (S)-6-(4-(4-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)butanoyl)piperazin-1-yl)nicotinonitrile 411

569.10 6-(4-(4-((6-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)methoxy)butanoyl)piperazin-1- yl)nicotinonitrile 412

555.10 6-(4-(3-((6-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)methoxy)propanoyl)piperazin-1- yl)nicotinonitrile  413*

520.10 (S)-6-(4-(3-((2-(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)propanoyl)piperazin-1-yl)nicotinonitrile  414*

520.10 (R)-6-(4-(3-((2-(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)propanoyl)piperazin-1-yl)nicotinonitrile  415*

564.10 (S)-4-Chloro-5-(1-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)methyl)isoindolin-2-yl)pyridazin-3(2H)- one  416*

564.10 (R)-4-Chloro-5-(1-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)methyl)isoindolin-2-yl)pyridazin-3(2H)- one 417*

452.05 (S)-5-(1-((3-Oxo-3-(piperazin-1-yl)propoxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  418*

452.05 (R)-5-(1-((3-Oxo-3-(piperazin-1-yl)propoxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 0.4 formic acid  419*

494.15 (S)-5-(1-((3-(4-Acetylpiperazin-1-yl)-3-oxopropoxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  420*

494.15 (R)-5-(1-((3-(4-Acetylpiperazin-1-yl)-3-oxopropoxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  421*

466.15 (S)-5-(1-((3-(4-Methylpiperazin-1-yl)-3-oxopropoxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  422*

466.15 (R)-5-(1-((3-(4-Methylpiperazin-1-yl)-3-oxopropoxy)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  423*

533.20 (S)-4-Oxo-4-(4-(3-((2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)propanoyl)piperazin-1-yl)butanenitrile 424*

533.20 (R)-4-Oxo-4-(4-(3-((2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methoxy)propanoyl)piperazin-1-yl)butanenitrile  425*

519.10 (R)-6-(4-(3-(((2-(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methyl)amino)propanoyl)piperazin-1- yl)nicotinonitrile  426*

519.10 (S)-6-(4-(3-(((2-(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methyl)amino)propanoyl)piperazin-1- yl)nicotinonitrile  427*

567.30 (S)-6-(4-(3-(Methyl((2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methyl)amino)propanoyl)piperazin-1- yl)nicotinonitrile  428*

567.30 (R)-6-(4-(3-(Methyl((2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methyl)amino)propanoyl)piperazin-1- yl)nicotinonitrile  429*

533.20 (S)-6-(4-(3-(((2-(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methyl)(methyl)amino)propanoyl)piperazin-1- yl)nicotinonitrile  430*

533.20 (R)-6-(4-(3-(((2-(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)isoindolin-1-yl)methyl)(methyl)amino)propanoyl)piperazin-1- yl)nicotinonitrile  431*

521.15 (S)-6-(4-(3-((6-(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)methoxy)propanoyl)piperazin-1- yl)nicotinonitrile  432*

521.15 (R)-6-(4-(3-((6-(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)methoxy)propanoyl)piperazin-1- yl)nicotinonitrile  433*

597.25 (S)-5-(1-(((3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)amino)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  434*

597.25 (R)-5-(1-(((3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)arnino)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 435

554.45 6-(4-(3-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)benzoyl)piperazin-1-yl)nicotinonitrile 436

558.05 4-(Trifluoromethyl)-5-(2-((3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)phenoxy)methyl)pyrrolidin-1-yl)pyridazin- 3(2H)-one 437

555.05 2-(4-(3-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)benzoyl)piperazin-1-yl)pyrimidine-5- carbonitrile  438*

555.10 (R)-2-(4-(3-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)benzoyl)piperazin-1-yl)pyrimidine-5- carbonitrile  439*

555.10 (S)-2-(4-(3-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)benzoyl)piperazin-1-yl)pyrimidine-5- carbonitrile 440

597.05 (S)-4-(Trifluoromethyl)-5-(2-((3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)phenoxy)methyl)pyrrolidin-1-yl)pyridazin- 3(2H)-one 441

598.10 (S)-4-(Trifluoromethyl)-5-(2-((3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenoxy)methyl)pyrrolidin-1-yl)pyridazin- 3(2H)-one 442

555.40 6-(4-(5-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)nicotinoyl)piperazin-1-yl)nicotinonitrile 443

555.05 (S)-5-(4-(3-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)benzoyl)piperazin-1-yl)pyrazine-2- carbonitrile 444

556.05 (S)-5-(4-(5-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)nicotinoyl)piperazin-1-yl)pyrazine-2- carbonitrile 445

530.10 (S)-5-(2-((3-(4-(Pyrimidin-2-yl)piperazine-1-carbonyl)phenoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 446

543.15 (S)-5-(2-((3-(4-(5-Methylpyridin-2-yl)piperazine-1-carbonyl)phenoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 447

544.15 (S)-5-(2-((3-(4-(5-Methylpyrimidin-2-yl)piperazine-1-carbonyl)phenoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 448

467.10 (S)-5-(2-((2-Oxo-2-(4-(pyridin-2-yl)piperazin-1-yl)ethoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethoyl)pyridazin-3(2H)-one 449

494.20 (S)-5-(2-((3-(4-Acetylpiperazine-1-carbonyl)phenoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 450

568.15 6-(3-methyl-4-(3-(((S)-1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)benzoyl)piperazin-1-yl)nicotinonitrile 451

490.20 (S)-5-(2-((3-(5,6,7,8-Tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)phenoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 452

579.25 6-(4-(3-(((2S,4S)-4-Cyano-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)benzoyl)piperazin-1- yl)nicotinonitrile 453

567.20 (S)-2-(4-(4-(3-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2- yl)methoxy)benzoyl)piperazin-1-yl)phenyl)acetonitrile 454

481.10 (S)-5-(2-((3-Oxo-3-(4-(pyridin-2-yl)piperazin-1-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 455

553.10 6-(4-(3-(((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2- yl)methyl)amino)benzoyl)piperazin-1-yl)nicotinonitrile 456

482.05 (S)-5-(2-((3-Oxo-3-(4-(pyrimidin-2-yl)piperazin-1-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 457

550.25 (S)-5-(2-((3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 458

549.20 (S)-5-(2-((3-Oxo-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one  459*

568.25 6-(4-(3-(((2R,3 S)-3-methyl-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)benzoyl)piperazin-1- yl)nicotinonitrile  460*

568.25 6-(4-(3-(((2S,3R)-3-methyl-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)benzoyl)piperazin-1- yl)nicotinonitrile 461

507.10 (S)-2-(4-(3-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)piperazin-1-yl)pyrimidine-5- carbonitrile 462

505.15 (S)-4-(4-(3-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)piperazin-1-yl)benzonitrile 463

506.10 (S)-2-(4-(3-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)piperazin-1-yl)nicotinonitrile 464

579.15 6-(4-(3-(((2S,4R)-4-Cyano-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)benzoyl)piperazin-1- yl)nicotinonitrile 465

598.30 6-(4-(4-(2-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-3-yl)methoxy)ethoxy)benzoyl)piperazin-1- yl)nicotinonitrile 466

550.10 6-(4-(3-(2-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-3-yl)methoxy)ethoxy)propanoyl)piperazin-1- yl)nicotinonitrile 467

598.20 6-(4-(3-(2-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-3-yl)methoxy)ethoxy)benzoyl)piperazin-1- yl)nicotinonitrile 468

472.10 (S)-6-(4-(3-((1-(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)piperazin-1-yl)nicotinonitrile 469

554.10 6-(4-(3-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-3-yl)methoxy)benzoyl)piperazin-1-yl)nicotinonitrile  470*

598.20 (R)-6-(4-(3-(2-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-3-yl)methoxy)ethoxy)benzoyl)piperazin-1- yl)nicotinonitrile  471*

598.20 (S)-6-(4-(3-(2-((1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-3-yl)methoxy)ethoxy)benzoyl)piperazin-1- yl)nicotinonitrile 472

302.10 (S)-5-(2-((prop-2-yn-1-yloxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 473

520.30 6-(3-Methyl-4-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)piperazin-1-yl)nicotinonitrile 474

507.30 (S)-5-(4-(3-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)piperazin-1-yl)pyrazine-2- carbonitrile 475

506.15 (S)-5-(4-(3-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)piperazin-1-yl)picolinonitrile 476

507.20 (S)-5-(4-(3-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)piperazin-1-yl)pyrimidine-2- carbonitrile 477

554.15 6-(4-(4-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-3-yl)methoxy)benzoyl)piperazin-1-yl)nicotinonitrile 478

536.10 6-(4-(2-(2-((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-3-yl)methoxy)ethoxy)acetyl)piperazin-1- yl)nicotinonitrile 479

594.10 (S)-6-(4-(4-(((1-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)methyl)cubane-1-carbonyl)piperazin-1- yl)nicotinonitrile 480

452.15 (S)-6-(4-(3-((1-(5-Methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)piperazin-1-yl)nicotinonitrile 481

515.25 (S)-5-(2-((3-(4-(5-Chloropyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 482

516.10 (S)-5-(2-((3-(4-(5-Chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 483

559.05 (S)-5-(2-((3-(4-(5-(Methylsulfonyl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 484

534.15 (S)-6-(4-(3-((4,4-Dimethyl-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)piperazin-1- yl)nicotinonitrile 485

521.25 6-(4-(3-(((2S,4S)-4-Amino-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)piperazin-1- yl)nicotinonitrile 486

521.25 6-(4-(3-(((2S,4R)-4-Amino-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)piperazin-1- yl)nicotinonitrile 487

521.25 6-(4-(3-(((3S,5S)-5-(Aminomethyl)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-3-yl)oxy)propanoyl)piperazin-1- yl)nicotinonitrile 488

602.10 6-(4-(3-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-4-yl)methoxy)benzoyl)piperazin-1-yl)nicotinonitrile 489

429.2 5-(5-((1-Acetylpiperidin-4-yl)methoxy)-6-fluoroisoindolin-2-yl)-4-isopropylpyridazin-3(2H)- one 490

570.15 6-(4-(2-(2-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-4-yl)oxy)ethoxy)acetyl)piperazin-1-yl)nicotinonitrile 491

569.05 6-(4-((2-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-4-yl)oxy)ethyl)glycyl)piperazin-1-yl)nicotinonitrile 492

583.25 6-(4-(3-((2-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-4-yl)oxy)ethyl)amino)propanoyl)piperazin-1- yl)nicotinonitrile 493

597.05 6-(4-(3-(Methyl(2-((2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-4-yl)oxy)ethyl)amino)propanoyl)piperazin-1- yl)nicotinonitrile 494

588.15 6-(4-(4-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-4-yl)oxy)benzoyl)piperazin-1-yl)nicotinonitrile 495

554.30 6-(4-(3-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-4-yl)methoxy)propanoyl)piperazin-1-yl)nicotinonitrile 496

568.30 6-(4-(4-((2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)isoindolin-4-yl)methoxy)butanoyl)piperazin-1-yl)nicotinonitrile 497

289.20 5-((4aR,7aR)-Octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one 498

289.20 5-((4aS,7aS)-Octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one ^(#)Absolute stereochemistryarbitrarily assigned. *The absolute stereochemistry was assigned basedon a protein X-ray crystal structure obtained of Example 18, isomer Bwhich confirmed (S)-absolute stereochemistry and was observed to be themore potent enantiomer.

Example 499:6-[4-[2-(2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)acetyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1:5-[(2-Hydroxyethyl)amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of Int-A6 (10 g, 30.4 mmol, 1 equiv), TEA (9.2 g, 90.9 mmol,2.989 equiv), 2-aminoethan-1-ol (2.1 g, 34.38 mmol, 1.130 equiv) in EtOH(100 mL) was stirred for 2 h at RT. The resulting mixture wasconcentrated under reduced pressure and crude residue purified by silicagel column eluting with EtOAc/petroleum ether (60/40) to afford 8.7 g(81%) of title compound as a yellow oil. LCMS: [M+H]⁺ 354.14.

Step 2: Ethyl2-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)acetate

A solution of5-[(2-hydroxyethyl)amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(3 g, 8.49 mmol, 1 equiv), Cs₂CO₃ (8.3 g, 25.47 mmol, 3.00 equiv), ethyl2-bromoacetate (4.2 g, 25.15 mmol, 2.96 equiv) in DMF (30 mL) wasstirred for 12 h at room temperature. The reaction was then quenched bythe addition of 20 mL of water. The resulting solution was extractedwith 3×30 mL of EtOAc and the organic layers combined and dried overanhydrous sodium sulfate. The organic layer was concentrated underreduced pressure and purified by silica gel chromatography eluting withEtOAc/petroleum ether (20/80) to afford 1 g (27%) of title compound as ayellow oil. LCMS: [M+H]⁺ 440.18.

Step 3:2-(2-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)aceticAcid

A solution of ethyl2-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)acetate(1 g, 2.28 mmol, 1 equiv), LiOH.H₂O (286 mg, 6.82 mmol, 3.00 equiv) inMeOH (20 mL) was stirred for 2 h at RT. The resulting solution wasextracted with 3×30 mL of ethyl acetate. The pH of the solution wasadjusted to 6 with HCl (35%) and the solids were collected by filtrationto afford 160 mg of the title compound (17%) as a yellow oil. LCMS:[M+H]⁺ 412.14.

Step 4:2-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethyl4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate

A solution of2-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)aceticacid (160 mg, 0.40 mmol, 1 equiv), DIPEA (100.8 mg, 0.78 mmol, 1.94equiv), EDCI (111.7 mg, 0.58 mmol, 1.45 equiv), HOBT (78.6 mg, 0.58mmol, 1.44 equiv), Int-A4 (95.4 mg, 0.51 mmol, 1.26 equiv) in DMF (4 mL)was stirred for 2 h at RT. After concentration, the residue was purifiedby C18 reverse phase chromatography eluting with H₂O/CH₃CN to afford 70mg (30.6%) of title compound as a white solid. LCMS: [M+H]⁺ 582.24.

Step 5:6-[4-[2-(2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)acetyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethyl4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate (70 mg, 0.12 mmol, 1equiv), TFA (0.25 mL) in DCM (5 mL) was stirred for 2 h at RT. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN and then the residue was furtherpurified by Prep-HPLC to afford the title compound as a white solid.LCMS: [M+H]⁺ 452.40. ¹H NMR (300 MHz, DMSO-d₆) δ: 12.46 (s, 1H), 8.52(d, J=2.3 Hz, 1H), 7.91 (d, J=10.3 Hz, 2H), 7.16 (s, 1H), 6.95 (d, J=9.2Hz, 1H), 4.29 (m, 2H), 3.73-3.54 (m, 10H), 3.47 (m, 2H).

Example 500:6-[4-[3-(2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of Int-A12 (1000 mg, 3.39 mmol, 1 equiv), DIPEA (1313.4 mg,10.16 mmol, 3 equiv), EDCI (974.0 mg, 5.08 mmol, 1.5 equiv), HOBT (686.6mg, 5.08 mmol, 1.5 equiv), Int-A4 (837.2 mg, 3.73 mmol, 1.1 equiv) inDMF (5 mL) was stirred for 1 h at RT. After concentration, the residuewas purified by C18 reverse phase chromatography eluting with H₂O/CH₃CNand the residue was further purified by Prep-HPLC to afford the titlecompound as a white solid (64.7 mg, 4.1%). LCMS: [M+H]⁺ 466.17. ¹H NMR(300 MHz, DMSO-d6) δ: 12.41 (s, 1H), 8.49 (d, J=2.3 Hz, 1H), 7.90-7.86(m, 2H), 6.96-6.83 (m, 2H), 3.65 (m, 6H), 3.53 (d, J=9.6 Hz, 8H), 2.57(t, J=6.4 Hz, 2H).

Example 501:6-[4-[3-(2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of Int-A11 (67 mg, 0.23 mmol, 1 equiv), DIPEA (87.7 mg, 0.68mmol, 3.00 equiv), EDCI (65.0 mg, 0.34 mmol, 1.5 equiv), HOBT (45.8 mg,0.34 mmol, 1.5 equiv), Int-A4 (55.9 mg, 0.25 mmol, 1.1 equiv) in DMF (3mL) was stirred for 3 h at RT. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN andfurther purified by Prep-HPLC to afford the title compound as a whitesolid (16.5 mg, 15.6%). LCMS: [M+H]⁺ 467.16. ¹H NMR (400 MHz, DMSO-d6)δ: 13.30 (s, 1H), 8.50 (d, J=2.3 Hz, 1H), 8.24 (s, 1H), 7.88 (dd, J=9.1,2.4 Hz, 1H), 6.92 (d, J=9.1 Hz, 1H), 4.57-4.48 (m, 2H), 3.77-3.51 (m,12H), 2.61 (t, J=6.5 Hz, 2H).

Example 502:6-(4-[3-[(2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethyl)amino]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1:6-(4-[3-[(2-Hydroxyethyl)amino]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of Int-A25 (400 mg, 1.65 mmol, 1 equiv) and 2-aminoethan-1-ol(5 mL) was stirred for 2 h at RT. The reaction was then quenched by theaddition of 10 mL of water. The resulting solution was extracted with3×20 mL of EtOAc and the organic layers combined and dried overanhydrous sodium sulfate. The organic layers were concentrated undervacuum. After concentration, the residue was purified by C18 reversephase chromatography eluting with H₂O/ACN to afford 270 mg (53.9%) oftitle compound as a yellow oil. LCMS: [M+H]⁺ 304.17.

Step 2: 5-Tert-butylN-[3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-3-oxopropyl]-N-(2-hydroxyethyl)carbamate

A solution of6-(4-[3-[(2-hydroxyethyl)amino]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile(270 mg, 0.89 mmol, 1 equiv), TEA (269.1 mg, 2.66 mmol, 2.99 equiv), and(Boc)₂O (233.1 mg, 1.07 mmol, 1.2 equiv) in DCM (15 mL) was stirred for3 h at RT. The reaction was then quenched by the addition of 20 mL ofwater. The organic layers were combined and dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford 350 mg (97%)of title compound as a yellow oil. LCMS: [M+H]⁺ 304.22.

Step 3: Tert-butylN-[3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-3-oxopropyl]-N-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]ethyl)carbamate

A solution of tert-butylN-[3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-3-oxopropyl]-N-(2-hydroxyethyl)carbamate(404 mg, 1.00 mmol, 1 equiv), Cs₂CO₃ (975 mg, 2.99 mmol, 2.99 equiv),Int-A6 (360.8 mg, 1.10 mmol, 1.10 equiv) in DMF (20 mL) was stirred for3 days at RT. The reaction was then quenched by the addition of 20 mL ofwater. The resulting solution was extracted with EtOAc and the organiclayers combined and dried over anhydrous sodium sulfate. The organiclayers were concentrated under vacuum and the residue was purified bysilica gel chromatography eluting with DCM/MeOH to afford 550 mg (79%)of title compound as a colorless oil. LCMS: [M+H]⁺ 696.31.

Step 4:6-(4-[3-[(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethyl)amino]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of tert-butylN-[3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-3-oxopropyl]-N-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]ethyl)carbamate(500 mg, 0.72 mmol, 1 equiv) and TFA (0.5 mL, 6.73 mmol, 9.37 equiv) inDCM (10 mL) was stirred for 2 h at RT. After concentration, the residuewas purified by C18 reverse phase chromatography eluting with H₂O/ACNfollowed by further purification by Prep-HPLC to afford the titlecompound (39.3 mg, 12%) as a white solid. LCMS: [M+H]⁺ 466.43; ¹H NMR(300 MHz, DMSO-d6) δ: 12.48 (s, 1H), 8.50 (d, J=2.3 Hz, 1H), 7.97 (s,1H), 7.90 (dd, J=9.1, 2.4 Hz, 1H), 6.95 (d, J=9.1 Hz, 1H), 4.77 (t,J=5.2 Hz, 1H), 3.74-3.60 (m, 6H), 3.55 (m, 6H), 3.44 (m, 2H), 2.70 (t,J=6.7 Hz, 2H).

Example 503:5-[(2-[3-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]ethyl)amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of Int-A12 (200 mg, 0.68 mmol, 1 equiv), Int-A3 (201 mg, 0.74mmol, 1.09 equiv), HATU (283.4 mg, 0.75 mmol, 1.1 equiv), DIPEA (262.7mg, 2.03 mmol, 3 equiv) in DMF (10 mL) was stirred for 1 h at 25° C.After concentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/ACN followed by further purification byPrep-HPLC to afford the title compound (82.4 mg, 26%) as a white solid.LCMS: [M+H]⁺ 476.13. ¹H NMR (400 MHz, DMSO-d₆) δ 12.40 (s, 1H), 8.44 (s,2H), 7.87 (s, 1H), 6.86 (s, 1H), 3.70 (dt, J=22.7, 5.8 Hz, 6H), 3.53(dd, J=10.6, 4.4 Hz, 8H), 2.59 (t, J=6.4 Hz, 2H).

The following examples in Table E2 were similarly prepared from theappropriate intermediates according to the method described for Example503.

TABLE E2 Example Name, structure, analytical data Int. Example 504

Int-A12 and Int-A185-[[2-(3-Oxo-3-[4-[5-(Trifluoromethyl)pyridin-2-yl]piperazin-1-yl]propoxy)ethyl]amino]-4-(trifluoromethyl)-2,3- dihydropyridazin-3-one;LCMS: [M + H]⁺ 509.17; ¹H NMR (300 MHz, DMSO-d₆) δ 12.34 (s, 1H),8.90-8.85 (s, 1H), 7.89 (m, 1H), 7.00-6.90 (m, 1H), 6.85 (s, 1H), 3.66(m, 14H), 2.57 (t, J = 6.4 Hz, 2H). Example 505

Int-A12 and Int-A2 5-[[2-(3-Oxo-3-[4-[5-(Trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)ethyl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one; LCMS: [M + H]⁺ 510.16; ¹H NMR (300 MHz,DMSO-d₆) δ: 12.43 (s, 1H), 8.74 (s, 2H), 7.89 (s, 1H), 6.89 (s, 1H),3.90 (m, 4H), 3.69 (t, J = 6.4 Hz, 2H), 3.57 (q, J = 3.6 Hz, 8H), 2.61(t, J = 6.4 Hz, 2H). Example 506

Int-A12 and Int-A5 5-[(2-[3-[4-(5-Chloropyridin-2-yl)piperazin-1-yl]-3-oxopropoxy]ethyl)amino]-4-(trifluoromethyl)-2,3- dihydropyridazin-3-one;LCMS: [M + H]⁺ 475.14; ¹H NMR (300 MHz, DMSO-d₆) δ 12.41 (s, 1H), 8.10(d, J = 2.7 Hz, 1H), 7.86 (s, 1H), 7.60 (dd, J = 9.1, 2.7 Hz, 1H), 6.86(d, J = 9.2 Hz, 2H), 3.65 (t, J = 6.3 Hz, 2H), 3.57-3.47 (m, 10H), 3.44(s, 2H), 2.56 (t, J = 6.4 Hz, 2H).

Example 507:6-[4-(3-[2-[(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)amino]ethoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of Int-A10 (100 mg, 0.38 mmol, 1.00 equiv), DMF (1 mL), DIPEA(148 mg, 1.15 mmol, 3.00 equiv), HATU (147 mg, 0.39 mmol, 1.01 equiv),and Int-A4 (72 mg, 0.38 mmol, 1.00 equiv) was stirred for 1 h at 25° C.After concentration under reduced pressure, the residue was purified bysilica gel column chromatography eluting with DCM/MeOH (92:8, v:v). Thesolution was concentrated under vacuum and the solids were collected byfiltration to afford the title compound (84.5 mg, 51%) as a white solid.LCMS: [M+H]⁺ 432.15. ¹H NMR (400 MHz, DMSO-d₆) δ: 12.54 (s, 1H), 8.51(s, 1H), 7.89-7.85 (m, 2H), 6.94-6.92 (d, J=8.8 Hz, 1H), 6.49 (s, 1H),3.69-3.66 (m, 6H), 3.55-3.50 (m, 8H), 2.61-2.58 (t, J=6.4 Hz, 2H).

The following examples in Table E3 were similarly prepared from Int-A10and the appropriate intermediates, respectively, Int-A2 and Int-A18according to the method described for Example 507.

TABLE E3 Example Name, structure, analytical data Int. Example 508

Int-A10 and Int-A24-Chloro-5-[[2-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)ethyl]amino]-2,3-dihydropyridazin-3-one; LCMS:[M + H]⁺ 476.15; ¹H NMR (400 MHz, DMSO-d₆) δ 12.54 (s, 1H), 8.73 (s,2H), 7.85 (s, 1H), 6 49 (t, J = 6.0 Hz, 1H), 3.83 (dt, J = 19.2, 4.9 Hz,4H), 3.68 (t, J = 6.4 Hz, 2H), 3.60-3.46 (m, 8H), 2.60 (t, J = 6.4 Hz,2H) Example 509

Int-A10 and Int-A184-Chloro-5-[[2-(3-oxo-3-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]propoxy)ethyl]amino]-2,3-dihydropyridazin- 3-one;LCMS: [M + H]⁺ 475.15; ¹H NMR (400 MHz, DMSO-d₆) δ 12.54 (s, 1H), 8.43(s, 1H), 7.84-7.81 (m, 2H), 6.96-6.94 (d, J = 8.8 Hz, 1H), 6.49 (s, 1H),3.67-3.46 (m, 14H), 2.60 (t, J = 6.0Hz, 2H).

Example 510:6-[4-[3-(2-[Methyl[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1:5-[(2-Hydroxyethyl)(methyl)amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of Int-A6 (2.0 g, 6.08 mmol, 1 equiv), TEA (1.2 g, 12.2 mmol,2 equiv), 2-(methylamino)ethan-1-ol (456.9 mg, 6.08 mmol, 1 equiv) inEtOH (10 mL) was stirred for 2 h at RT. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (50/50, v/v) to afford 1600 mg(72%) of title compound as a yellow oil. LCMS: [M+H]⁺ 368.15.

Step 2: Methyl3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)propanoate

A solution of5-[(2-hydroxyethyl)(methyl)amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1.6 g, 4.35 mmol, 1.00 equiv), methyl prop-2-enoate (750 mg, 8.71 mmol,2.00 equiv), Cs₂CO₃ (2.8 g, 8.59 mmol, 2.00 equiv) in ACN (100 mL) wasstirred for 14 h at RT. The resulting mixture was concentrated underreduced pressure and the residue was applied onto a silica gel columneluting with EtOAc/petroleum ether (1:4) to afford 600 mg (30%) of titlecompound as a yellow oil. LCMS: [M+H]⁺ 454.19.

Step 3: Methyl3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)propanoate

A solution of methyl3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)propanoate(660 mg, 1.46 mmol, 1 equiv) in DCM (5 mL) and TFA (0.5 mL) was stirredfor 2 h at RT. The reaction was then quenched by the addition of 5 mL ofwater. The resulting solution was extracted with 3×30 mL of DCM and theorganic layers combined and dried over anhydrous sodium sulfate. Theresulting mixture was concentrated under vacuum to afford 489 mg of thetitle compound as a yellow oil. LCMS: [M+H]⁺ 324.11.

Step 4:3-(2-[Methyl[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)propanoicAcid

A solution of methyl3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)propanoate(489 mg, 1.51 mmol, 1 equiv), LiOH.H₂O (317.4 mg, 7.56 mmol, 5.00 equiv)in MeOH (5 mL) and H₂O (1 mL) was stirred for 3 h at RT. The pH value ofthe solution was adjusted to 7 with HCl (2M). After concentration, theresidue was purified by C18 reverse phase chromatography eluting withH₂O/ACN to afford 469 mg of title compound as a yellow oil. LCMS: [M+H]⁺310.09.

Step 5:6-[4-[3-(2-[Methyl[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)propanoicacid (469 mg, 1.52 mmol, 1 equiv), Int-A4 (340.8 mg, 1.52 mmol, 1equiv), HOBT (307.4 mg, 2.27 mmol, 1.5 equiv), EDCI (436.1 mg, 2.27mmol, 1.5 equiv), and DIPEA (588.0 mg, 4.55 mmol, 3 equiv) in DMF (2 mL)was stirred for 2 h at 30° C. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/ACN andfurther purified by Prep-HPLC to afford the title compound (80.6 mg,11%) as a white solid. LCMS: [M+H]⁺ 480.19. ¹H NMR (400 MHz, DMSO-d₆) δ12.43 (s, 1H), 8.50 (d, J=2.2 Hz, 1H), 7.94-7.87 (m, 2H), 6.92 (d, J=9.1Hz, 1H), 3.61 (ddd, J=29.4, 20.2, 14.0 Hz, 14H), 3.02 (s, 3H), 2.56 (d,J=6.3 Hz, 2H).

Example 511:6-[4-(6-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]hexanoyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Tert-butylN-[6-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-6-oxohexyl]carbamate

A solution of 6-[[(tert-butoxy)carbonyl]amino]hexanoic acid (1 g, 4.32mmol, 1.00 equiv), HATU (1.6 g, 4.21 mmol, 1.00 equiv), DIPEA (2.2 g,17.02 mmol, 4.00 equiv), Int-A4 (814 mg, 4.32 mmol, 1.00 equiv) in DMF(5 mL) was stirred for 1 h at RT. The resulting solution was extractedwith 3×30 mL of diethyl ether and the organic layers combined andconcentrated under reduced pressure to afford 1.5 g (86%) of titlecompound as a white solid. LCMS: [M+H]⁺ 402.24.

Step 2: 6-[4-(6-Aminohexanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of tert-butylN-[6-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-6-oxohexyl]carbamate (1.5g, 3.74 mmol, 1.00 equiv) in HCl/dioxane (20 mL) was stirred for 2 h atRT. The resulting mixture was concentrated under reduced pressure toafford 1 g (89%) of title compound as a yellow oil. LCMS: [M+H]⁺ 302.19.

Step 3:6-[4-(6-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]hexanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-(6-aminohexanoyl)piperazin-1-yl]pyridine-3-carbonitrile (500 mg,1.66 mmol, 1.00 equiv), TEA (335 mg, 3.31 mmol, 2.00 equiv), and Int-A6(544 mg, 1.65 mmol, 1.00 equiv) in EtOH (10 mL) was stirred for 2 h at60° C. After concentration, the residue was purified by silica gelchromatography eluting with EtOAc/petroleum ether (1/1) to afford 252 mg(26%) of title compound as a yellow solid. LCMS: [M+H]⁺ 594.28.

Step 4:6-[4-(6-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]hexanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-(6-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]hexanoyl)piperazin-1-yl]pyridine-3-carbonitrile(252 mg, 0.42 mmol, 1.00 equiv) and TFA (3 mL) in DCM (12 mL) wasstirred for 1 h at RT. After concentration, the residue was purified byC18 reverse phase chromatography eluting with H₂O/ACN to afford thetitle compound (94.4 mg, 48%) as a white solid. LCMS: [M+H]⁺ 464.19. ¹HNMR (300 MHz, CD₃OD) δ 8.42 (dd, J=2.4, 0.8 Hz, 1H), 7.89 (d, J=0.7 Hz,1H), 7.76 (dd, J=9.1, 2.4 Hz, 1H), 6.86 (dd, J=9.1, 0.9 Hz, 1H), 3.79(dd, J=6.5, 3.8 Hz, 2H), 3.74-3.62 (m, 6H), 3.42 (t, J=7.1 Hz, 2H), 2.47(t, J=7.4 Hz, 2H), 1.76-1.59 (m, 4H), 1.44 (qd, J=9.9, 9.1, 5.7 Hz, 2H).

Example 512:6-[4-(6-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]hexanoyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1: 6-[4-(6-Hydroxyhexanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of 6-hydroxyhexanoic acid (500 mg, 3.78 mmol, 1.00 equiv),HATU (1.43 g, 3.76 mmol, 1.00 equiv), DIPEA (1.46 g, 11.30 mmol, 3.00equiv) and Int-A4 (1.06 g, 5.63 mmol, 1.50 equiv) in DMF (10 mL) wasstirred for 2 h at RT. The resulting solution was diluted with 30 mL ofH₂O and extracted with 3×30 mL of EtOAc. The organic layer was combined,washed with 1×20 mL of brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by asilica gel column eluting with EtOAc/petroleum ether (7/3, v/v) toafford 1.06 g (93%) of title compound as a yellow oil. LCMS: [M+H]⁺303.17.

Step 2:6-[4-(6-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]hexanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-(6-hydroxyhexanoyl)piperazin-1-yl]pyridine-3-carbonitrile (600 mg,1.98 mmol, 1.00 equiv), Cs₂CO₃ (1.29 g, 3.96 mmol, 2.00 equiv) andInt-A6 (651 mg, 1.98 mmol, 1.00 equiv) in ACN (10 mL) was stirred for 15h at 40° C. The resulting solution was diluted with 20 mL of H₂O,extracted with 3×20 mL of EtOAc and the organic layer was combined,washed with 1×20 mL of brine and concentrated under reduced pressure.The residue was purified by silica gel column chromatography elutingwith EtOAc/petroleum ether (7/3, v/v) to afford 240 mg (20%) of titlecompound as a yellow oil. LCMS: [M+H]⁺ 595.26.

Step 3:6-[4-(6-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]hexanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-(6-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]hexanoyl)piperazin-1-yl]pyridine-3-carbonitrile(370 mg, 0.62 mmol, 1.00 equiv) and TFA (2 mL) in DCM (10 mL) wasstirred for 2 h at RT. After concentration, the residue was purified byC18 reverse phase chromatography eluting with H₂O/CH₃CN to afford thetitle compound (68.5 mg, 24%) as a white solid. LCMS: [M+H]⁺ 465.00. ¹HNMR (300 MHz, Methanol-d4) δ 8.44 (s, 1H), 8.21 (s, 1H), 7.79 (dd,J=9.0, 2.4 Hz, 1H), 6.90 (dd, J=9.0, 0.6 Hz, 1H), 4.44 (t, J=6.0 Hz,2H), 3.83-3.68 (m, 8H), 2.53 (t, J=7.2 Hz, 2H), 1.93 (dt, J=13.7, 6.4Hz, 2H), 1.77-1.67 (m, 2H), 1.62-1.51 (m, 2H).

Example 513 Isomer A:(S)-6-(4-(3-(2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)propanoyl)piperazin-1-yl)nicotinonitrileand Example 513 Isomer B:(R)-6-(4-(3-(2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)propanoyl)piperazin-1-yl)nicotinonitrile

Step 1: Methyl 3-(2-[[(tert-butoxy)carbonyl]amino]propoxy)propanoate

A solution of tert-butyl N-(1-hydroxypropan-2-yl)carbamate (3.15 g, 18.0mmol, 1.00 equiv), Na (100 mg), and methyl prop-2-enoate (1.7 g, 20.0mmol, 1.10 equiv) in THF (40 mL) was stirred for 2 h at RT. Theresulting mixture was concentrated under reduced pressure. The residuewas purified by silica gel column chromatography eluting withDCM/petroleum ether (1:10) to afford 1.5 g (32%) of title compound as awhite oil. LCMS: [M+H]⁺ 262.16.

Step 2: Methyl 3-(2-aminopropoxy)propanoate Hydrochloride

A solution of methyl3-(2-[[(tert-butoxy)carbonyl]amino]propoxy)propanoate (1.38 g, 5.28mmol, 1.00 equiv) in HCl/dioxane (10 mL) was stirred for 2 h at RT. Thesolvent was concentrated under reduced pressure to afford 1 g (95%) oftitle compound as a white oil. LCMS: [M+H]⁺ 162.15

Step 3: Methyl3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoate

A solution of methyl 3-(2-aminopropoxy)propanoate hydrochloride (1 g,5.06 mmol, 1.00 equiv), TEA (2 mL), and Int-A6 (1.64 g, 4.99 mmol, 1.00equiv) in EtOH (10 mL) was stirred for 2 h at 60° C. The resultingmixture was concentrated under vacuum. The residue was purified bysilica gel column chromatography eluting with EtOAc/petroleum ether(1:5) to afford 1 g (44%) of title compound as a white oil. LCMS: [M+H]⁺454.19.

Step 4:3-(2-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoicAcid

A solution of ethyl3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoate(400 mg, 0.86 mmol, 1.00 equiv), water (5 mL), and LiOH (103 mg, 4.30mmol, 5.00 equiv) in MeOH (15 mL) was stirred for 2 h at RT. Theresulting mixture was concentrated under vacuum to afford 460 mg oftitle compound as a yellow solid. LCMS: [M+H]⁺ 440.18.

Step 5:6-[4-[3-(2-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoicacid (460 mg, 1.05 mmol, 1.00 equiv), HATU (520 mg, 1.37 mmol, 1.30equiv), DIPEA (271 mg, 2.10 mmol, 2.00 equiv), and Int-A4 (197 mg, 1.05mmol, 1.00 equiv) in DMF (15 mL) was stirred for 2 h at RT. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column eluting with EtOAc/petroleum ether (1:1) toafford 350 mg (55%) of title compound as a yellow oil. LCMS: [M+H]⁺610.28.

Step 6:(S)-6-(4-(3-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)propanoyl)piperazin-1-yl)nicotinonitrileand(R)-6-(4-(3-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino)propoxy)propanoyl)piperazin-1-yl)nicotinonitrile

A solution of6-[4-[3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile(350 mg, 0.57 mmol, 1.00 equiv), TFA (1 mL) in DCM (5 mL) was stirredfor 0.5 h at RT. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/ACN. The residue wasfurther purified by Prep-HPLC and Chiral-Prep-HPLC (CHIRALPAK IG-3, 3rpm, 0.46×10 cm column, eluting with a gradient of MtBE (0.1%DEA):EtOH=70:30, at a flow rate of 1 mL/min) to afford the titlecompounds as white solids. The absolute stereochemistry was assignedbased on a protein X-ray crystal structure obtained of Example 513A,which confirmed (S)-absolute stereochemistry of the more potentenantiomer.

Example 513 Isomer A

10.9 mg, 8%, LCMS: [M+H]⁺ 480.15. ¹H NMR (300 MHz, Methanol-d₄) δ 8.43(dd, J=2.4, 0.8 Hz, 1H), 7.95 (s, 1H), 7.77 (dd, J=9.1, 2.4 Hz, 1H),6.86 (dd, J=9.1, 0.8 Hz, 1H), 4.21-4.12 (m, 1H), 3.91-3.79 (m, 4H),3.78-3.60 (m, 7H), 3.56-3.51 (m, 1H), 2.70 (t, J=6.0 Hz, 2H), 1.27 (d,J=6.6 Hz, 3H). tR=2.492 min.

Example 513 Isomer B

9.3 mg, 7%, LCMS: [M+H]⁺ 480.15. tR=3.349 min.

Example 514 Isomer A:6-(4-[3-[(2R)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2-phenylethoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 514 Isomer B:6-(4-[3-[(2S)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2-phenylethoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1: Methyl3-(2-[[(tert-butoxy)carbonyl]amino]-2-phenylethoxy)propanoate

A solution of tert-butyl N-(2-hydroxy-1-phenylethyl)carbamate (1 g, 4.21mmol, 1.00 equiv), methyl prop-2-enoate (1.8 g, 20.91 mmol, 5.00 equiv)and Cs₂CO₃ (2.7 g, 8.29 mmol, 2.00 equiv) in ACN (20 mL) was stirred for1 h at RT. The solid was filtered out and the resulting solution wasdiluted with 150 mL of H₂O, and extracted with 3×50 mL of EtOAc. Theorganic layers were combined, dried over anhydrous sodium sulfate andconcentrated under vacuum to afford 1.3 g (95%) of title compound as ayellow oil. LCMS: [M+H]⁺ 324.7.

Step 2: 3-(2-[[(Tert-butoxy)carbonyl]amino]-2-phenylethoxy)propanoicAcid

A solution of methyl3-(2-[[(tert-butoxy)carbonyl]amino]-2-phenylethoxy)propanoate (324 mg,1.00 mmol, 1.00 equiv) and LiOH (84 mg, 3.51 mmol, 2.00 equiv) in THF (5mL) and water (0.5 mL) was stirred for 2 h at RT. The resulting solutionwas concentrated under vacuum, and then the residue was diluted with 20mL of H₂O, and extracted with 3×20 mL of EtOAc. The organic layers werecombined, dried over anhydrous sodium sulfate, and concentrated undervacuum to afford 300 mg (97%) of title compound as a yellow oil. LCMS:[M+H]⁺ 310.16.

Step 3: Tert-butylN-(2-[3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-3-oxopropoxy]-1-phenylethyl)carbamate

A solution of3-(2-[[(tert-butoxy)carbonyl]amino]-2-phenylethoxy)propanoic acid (300mg, 0.97 mmol, 1.00 equiv), HATU (366 mg, 0.96 mmol, 1.00 equiv), Int-A4(180 mg, 0.96 mmol, 1.00 equiv) and DIPEA (249 mg, 1.93 mmol, 2.00equiv) in DMF (3 mL) was stirred for 1 h at RT. The resulting solutionwas diluted with 60 mL of EtOAc and washed with 3×20 mL of H₂O. Theorganic layers were dried over anhydrous sodium sulfate and concentratedunder vacuum to afford 560 mg of title compound as a yellow crude oil.LCMS: [M+H]⁺ 480.25.

Step 4:6-[4-[3-(2-Amino-2-phenylethoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of tert-butylN-(2-[3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-3-oxopropoxy]-1-phenylethyl)carbamate(560 mg, 1.17 mmol, 1.00 equiv) and TFA (1 mL) in DCM (5 mL) was stirredfor 1 h at RT. The resulting solution was concentrated under vacuum toafford 380 mg (86%) of title compound as a yellow crude oil. LCMS:[M+H]⁺ 380.20.

Step 5:6-[4-[3-(2-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]-2-phenylethoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-[3-(2-amino-2-phenylethoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile(380 mg, 1.00 mmol, 1.00 equiv), Int-A6 (329 mg, 1.00 mmol, 1.00 equiv)and Cs₂CO₃ (652 mg, 2.00 mmol, 2.00 equiv) in ACN (20 mL) was stirredfor 1 h at 80° C. The solids were filtered and the resulting solutionwas concentrated under vacuum. The residue was purified by silica gelcolumn chromatography eluting with EtOAc/petroleum ether to afford 120mg (18%) of title compound as a yellow oil. LCMS: [M+H]⁺ 672.29.

Step 6:6-(4-[3-[(2R)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2-phenylethoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrileand of6-(4-[3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2-phenylethoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of 6-[4-[3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]-2-phenylethoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile(100 mg, 0.15 mmol, 1.00 equiv) and TFA (0.5 mL) in DCM (2.5 mL) wasstirred for 1 h at RT. After concentration, the residue was purified byC18 reverse phase chromatography eluting with H₂O/CH₃CN. Then theresidue was further purified by Prep-HPLC and Chiral-Prep-HPLC (CHIRALCellulose-SB, 3 μm, 0.46×15 cm column, eluting with a gradient of MtBE(0.1% DEA):EtOH=50:50, at a flow rate of 1 mL/min) to afford the titlecompounds, respectively, as white solids. The absolute stereochemistrywas assigned in analogy to Example 513A, based on the PARP7 potency ofthe more potent enantiomer and in analogy to the Example 513A X-ray.

Example 514 Isomer A

10.7 mg, 35%, LCMS: [M+H]⁺ 542.25. ¹H NMR (300 MHz, Methanol-d₄) δ 8.44(d, J=1.8 Hz, 1H), 7.79 (dd, J=9.0, 2.4 Hz, 1H), 7.58 (s, 1H), 7.45-7.32(m, 5H), 6.87 (d, J=9.0 Hz, 1H), 5.08-5.06 (m, 1H), 3.91-3.72 (m, 12H),2.75 (t, J=5.4 Hz, 2H). tR=2.982 min.

Example 514 Isomer B

10.0 mg, 36%, LCMS: [M+H]⁺ 542.25. tR=3.850 min.

Example 515 Isomer A:6-(4-[3-[(2R)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2-phenylethoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 515 Isomer B:6-(4-[3-[(2S)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2-phenylethoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1: Methyl3-(2-[[(tert-butoxy)carbonyl]amino]-3-phenylpropoxy)propanoate

A solution of tert-butyl N-(1-hydroxy-3-phenylpropan-2-yl)carbamate(2.51 g, 9.99 mmol, 1.00 equiv), NaH (600 mg, 25.0 mmol, 1.10 equiv),and methyl 3-bromopropanoate (1.8 g, 10.8 mmol, 1.10 equiv) in THF (30mL) was stirred for 3 h at RT. The solvent was concentrated under vacuumand the residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1:5) to afford 1.2 g (36%) of title compound as awhite solid. LCMS: [M+H]⁺ 338.20.

Step 2: 3-(2-[[(Tert-butoxy)carbonyl]amino]-3-phenylpropoxy)propanoicAcid

A solution of methyl3-(2-[[(tert-butoxy)carbonyl]amino]-3-phenylpropoxy)propanoate (1.2 g,3.56 mmol, 1.00 equiv), LiOH (420 mg, 17.54 mmol, 5.00 equiv), water (2mL) in MeOH (20 mL) was stirred for 12 h at RT. The pH value of thesolution was adjusted to 5 with HCl (36%). The resulting solution wasextracted with EtOAc (3×30 mL) and the organic layers combined. Thesolution was dried over anhydrous sodium sulfate and concentrated undervacuum to afford 1 g of the title compound as a yellow oil. LCMS: [M+H]⁺324.20.

Step 3: 3-(2-Amino-3-phenylpropoxy)propanoic Acid Hydrochloride

A solution of3-(2-[[(tert-butoxy)carbonyl]amino]-3-phenylpropoxy)propanoic acid (1 g,3.09 mmol, 1.00 equiv) in HCl/dioxane (10 mL) was stirred for 1 h at RT.The resulting mixture was concentrated under vacuum to afford 800 mg ofthe title compound as a yellow oil. LCMS: [M+H]⁺ 324.20.

Step 4:3-(2-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]-3-phenylpropoxy)propanoicAcid

A solution of 3-(2-amino-3-phenylpropoxy)propanoic acid hydrochloride(800 mg, 3.08 mmol, 1.00 equiv), TEA (2 mL), and Int-A6 (1 g, 3.04 mmol,1.00 equiv) in EtOH (10 mL) was stirred for 3 h at 60° C. The solventwas concentrated under vacuum and the residue was purified by silica gelcolumn chromatography eluting with EtOAc/petroleum ether (1:1) to afford1 g (63%) of title compound as a yellow oil. LCMS: [M+H]⁺ 516.20.

Step 5:6-[4-[3-(2-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]-3-phenylpropoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]-3-phenylpropoxy)propanoicacid (1.29 g, 2.50 mmol, 1.00 equiv), HATU (1.43 g, 3.76 mmol, 1.50equiv), DIPEA (0.8 mL), and Int-A4 (470 mg, 2.50 mmol, 1.00 equiv) inDMF (3 mL) was stirred for 1 h at RT. After concentration, the residuewas purified by C18 reverse phase chromatography eluting with H₂O/ACN toafford 430 mg (25%) of title compound as a white oil. LCMS: [M+H]⁺686.31.

Step 6:6-(4-[3-[(2R)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2-phenylethoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrileand6-(4-[3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2-phenylethoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of 6-[4-[3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]-2-phenylethoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile(180 mg, 0.27 mmol, 1.00 equiv) and TFA (2 mL) in DCM (12 mL) wasstirred for 1 h at RT. After concentration, the residue was purified byC18 reverse phase chromatography eluting with H₂O/ACN. The residue wasfurther purified by Prep-HPLC and Chiral-Prep-HPLC (CHIRALPAK IC-3, 3μm, 0.46×10 cm column, eluting with a gradient of MtBE (0.1%DEA):EtOH=50:50, at a flow rate of 1 mL/min) to afford the titlecompounds as white solids. The absolute stereochemistry was assigned inanalogy to Example 513A, based on the PARP7 potency of the more potentenantiomer and in analogy to the Example 513A X-ray.

Example 515 Isomer A

10.0 mg, 6%, LCMS: [M+H]⁺ 556.10. ¹H NMR (300 MHz, CD₃OD-d₄) δ 8.43 (s,1H), 7.77 (dd, J=9.1, 2.3 Hz, 1H), 7.64 (s, 1H), 7.31-7.21 (m, 5H), 6.86(dd, J=9.1, 0.8 Hz, 1H), 4.30 (s, 1H), 3.86-3.79 (m, 4H), 3.77-3.57 (m,8H), 3.02-2.96 (m, 1H), 2.90-2.83 (m, 1H), 2.73 (t, J=5.9 Hz, 2H).tR=2.227 min.

Example 515 Isomer B

16.6 mg, 9%, LCMS: [M+H]⁺: 556.10. tR=4.973 min.

Example 516:6-(4-[3-[Methyl(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethyl)amino]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1:6-(4-[3-[(2-Hydroxyethyl)(methyl)amino]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of Int-A25 (2.3 g, 9.5 mmol, 1 equiv) and2-(methylamino)ethan-1-ol (1.4 g, 18.6 mmol, 1.96 equiv) in EtOH (20 mL)was stirred for 2 hr at 60° C. The solvent was concentrated under vacuumand the residue was purified by silica gel column chromatography elutingwith DCM/MeOH (9/1) to afford 1.4 g of title compound as a yellow oil.LCMS: [M+H]⁺ 318.19.

Step 2:6-(4-[3-[Methyl(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]ethyl)amino]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-(4-[3-[(2-hydroxyethyl)(methyl)amino]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile(1.4 g, 4.4 mmol, 1 equiv), Cs₂CO₃ (2.86 g, 8.8 mmol, 1.99 equiv), andInt-A6 (1.7 g, 5.2 mmol, 1.2 equiv) in DMF (20 mL) was stirred for 2days at RT. The reaction was then quenched by the addition of 20 mL ofwater. The resulting solution was extracted with 3×30 mL of EtOAc andthe organic layers combined and dried over anhydrous sodium sulfate. Theorganic layers were concentrated under vacuum. The residue was purifiedby silica gel column chromatography diluting with DCM/MeOH (4/1) toafford 640 mg (24%) of title compound as a yellow oil. LCMS: [M+H]⁺610.27.

Step 3:6-(4-[3-[Methyl(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethyl)amino]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-(4-[3-[methyl(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]ethyl)amino]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile(250 mg, 0.41 mmol, 1 equiv) and TFA (1 mL) in DCM (10 mL) was stirredfor 1 hr at RT. The solvent was concentrated under vacuum and theresidue was purified by C18 reverse phase chromatography eluting withH₂O/ACN followed by further purification by Prep-TLC to afford the titlecompound (11.0 mg, 5.6%) as a white solid. LCMS: [M+H]⁺ 480.1. ¹H NMR(300 MHz, DMSO-d₆) δ 13.28 (s, 1H), 8.51 (d, J=2.3 Hz, 1H), 8.27 (d,J=0.9 Hz, 1H), 7.89 (dd, J=9.1, 2.4 Hz, 1H), 6.94 (d, J=9.1 Hz, 1H),4.46 (t, J=5.4 Hz, 2H), 3.75-3.52 (m, 8H), 2.78-2.61 (m, 4H), 2.51-2.43(m, 2H), 2.25 (s, 3H).

Example 517:6-(4-(2-(3-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yloxy)propoxy)acetyl)piperazin-1-yl)nicotinonitrile

Step 1: 6-[4-(2-Bromoacetyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of 2-bromoacetyl bromide (1 g, 4.95 mmol, 1.00 equiv), Int-A4(945 mg, 5.02 mmol, 1.00 equiv), and TEA (1.275 g, 12.60 mmol, 2.50equiv) in DCM (15 mL) was stirred for 0.5 h at RT. The solids werefiltered and the resulting solution was concentrated under vacuum toafford 1.5 g of title compound as a yellow oil. LCMS: [M+H]⁺ 309.03.

Step 2:6-[4-[2-(3-Hydroxypropoxy)acetyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of propane-1,3-diol (108.57 mg, 1.43 mmol, 2.00 equiv),6-[4-(2-bromoacetyl)piperazin-1-yl]pyridine-3-carbonitrile (220 mg, 0.71mmol, 1.00 equiv), and Cs₂CO₃ (692.3 mg, 2.12 mmol, 3.00 equiv) in DMF(10 mL) was stirred for 3 h at RT. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/ACN toafford 81 mg (37%) of title compound as a yellow solid. LCMS: [M+H]⁺305.15.

Step 3:6-[4-[2-(3-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]propoxy)acetyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-[2-(3-hydroxypropoxy)acetyl]piperazin-1-yl]pyridine-3-carbonitrile(76 mg, 0.25 mmol, 1.00 equiv), Int-A6 (98.4 mg, 0.30 mmol, 1.20 equiv),and Cs₂CO₃ (243.8 mg, 0.75 mmol, 3.00 equiv) in DMF (5 mL) was stirredfor 2.5 h at 80° C. The solids were filtered and the resulting solutionwas extracted with EtOAc (3×30 mL) and the organic layers combined. Thesolution was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied by silica gel column chromatographyeluting with EtOAc/hexane (1:2) to afford 40 mg (27%) of title compoundas a yellow oil. LCMS: [M+H]⁺ 597.24.

Step 4:6-(4-(2-(3-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yloxy)propoxy)acetyl)piperazin-1-yl)nicotinonitrile

A solution of 6-[4-[2-(3-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]propoxy)acetyl]piperazin-1-yl]pyridine-3-carbonitrile(55 mg, 0.09 mmol, 1.00 equiv) and TFA (1 mL) in DCM (5 mL) was stirredfor 1 h at RT. After concentration, the residue was purified byPrep-HPLC eluting with H₂O/ACN to afford the title compound (8.4 mg,20%) as a white solid. LCMS: [M+H]⁺ 467.05. ¹H NMR (300 MHz,Methanol-d₄) δ 8.44 (s, 1H), 8.24 (s, 1H), 7.77 (dd, J=9.2, 6.3 Hz, 1H),6.87 (d, J=9.0 Hz, 1H), 4.55 (t, J=6.3 Hz, 2H), 4.30 (s, 2H), 3.72-3.78(m, 8H), 3.70-3.61 (m, 2H), 2.10-2.18 (m, 2H).

Example 518 Isomer A:(R)-6-(4-(3-(3-Methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazin-1-yl)nicotinonitrileand Example 518 Isomer B:(S)-6-(4-(3-(3-Methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazin-1-yl)nicotinonitrile

Step 1:3-Methoxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propanoicAcid

A solution of Int-A6 (3 g, 9.12 mmol, 1.00 equiv),2-amino-3-methoxypropan-1-ol (1.2 g, 11.41 mmol, 1.00 equiv), and TEA (6mL) in EtOH (20 mL) was stirred for 1 h at 50° C. The solvent wasconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography eluting with DCM/MeOH (3/1) to afford2.8 g (75%) of title compound as a red solid. LCMS: [M+H]⁺ 412.25.

Step 2:5-[(1-Hydroxy-3-methoxypropan-2-yl)amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propanoicacid (3 g, 7.29 mmol, 1.00 equiv) in B₂H₆.THF (35 mL, 5.00 equiv) wasstirred for 2 h at 50° C. The reaction was then quenched by the additionof 20 mL of MeOH. The solvent was concentrated under reduced pressureand the residue was purified by silica gel column chromatography elutingwith EtOAc/petroleum ether (3/2) to afford 800 mg (28%) of titlecompound as a yellow oil. LCMS: [M+H]⁺ 398.35.

Step 3: Methyl3-(3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoate

A solution of5-[(1-hydroxy-3-methoxypropan-2-yl)amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(600 mg, 1.51 mmol, 1.00 equiv), methyl prop-2-enoate (600 mg, 7.0 mmol,5.0 equiv), and Cs₂CO₃ (900 mg, 2.8 mmol, 2.00 equiv) in ACN (20 mL) wasstirred overnight at 35° C. The resulting mixture was concentrated underreduced pressure and the residue purified by silica gel columnchromatography eluting with EtOAc/petroleum ether to afford 150 mg (21%)of title compound as a yellow oil. LCMS: [M+H]⁺ 484.15.

Step 4: Methyl3-(3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoate

A solution of methyl3-(3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoate(150 mg, 0.31 mmol, 1.00 equiv) in dioxane/HCl (4M, 4 mL) was stirredfor 4 h at 25° C. The resulting mixture was concentrated under vacuum toafford 120 mg of title compound as a colorless oil. LCMS: [M+H]⁺ 354.20.

Step 5:3-(3-Methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoicacid

A solution of methyl3-(3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoate(120 mg, 0.34 mmol, 1.00 equiv), and LiOH (100 mg, 4.18 mmol, 10.0equiv) in MeOH (5 mL) and water (2 mL) was stirred overnight at 25° C.After concentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/ACN to afford 50 mg (43%) of titlecompound as a yellow oil. LCMS: [M+H]⁺ 340.20.

Step 6:(R)-6-(4-(3-(3-Methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazin-1-yl)nicotinonitrileand(S)-6-(4-(3-(3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazin-1-yl)nicotinonitrile

A solution of3-(3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoicacid (50 mg, 0.15 mmol, 1.00 equiv), Int-A4 (35 mg, 0.16 mmol, 1.00equiv), HATU (56 mg, 0.15 mmol, 1.00 equiv), and DIPEA (1 mL) in DMF (3mL) was stirred for 1 h at 25° C. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/ACN andfurther purified by Prep-HPLC. The enantiomers were separated by chiralPrep-HPLC (CHIRAL Cellulose-SB, 5 μm, 0.46×15 cm column, eluting with agradient of Hexanes (0.1% DEA):EtOH=50:50, at a flow rate of 1 mL/min)to afford the title compounds as white solids. The absolutestereochemistry was assigned in analogy to Example 513A, based on thePARP7 potency of the more potent enantiomer and in analogy to theExample 513A X-ray.

Example 518 Isomer A

3.5 mg, 23%, LCMS: [M+H]⁺ 510.15. ¹H NMR (400 MHz, DMSO-d₆) δ 12.49 (s,1H), 8.04 (d, J=2.4 Hz, 1H), 7.93 (s, 1H), 7.90-7.87 (dd, J=8.80, 2.20Hz, 1H), 6.92 (d, J=9.2 Hz, 1H), 6.23-6.22 (dd, J=8.80, 4.80 Hz, 1H),4.27 (s, 1H), 3.69-3.53 (m, 14H), 3.27 (s, 3H), 2.60-2.57 (m, 2H).tR=1.080 min.

Example 518 Isomer B

4.3 mg, 29%, LCMS: [M+H]⁺ 510.15, tR=1.073 min.

Example 519:6-[4-[3-(2-Methyl-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1:3-Methoxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propanoicAcid

A solution of tert-butyl N-(1-hydroxy-2-methylpropan-2-yl)carbamate(3.78 g, 20.0 mmol, 1.00 equiv) in HCl/dioxane (40 mL) was stirred for 1h at 25° C. The solids were collected by filtration to afford the titlecompound (2.2 g, 68%) as a white solid. LCMS: [M−Cl]⁺ 90.08.

Step 2:5-[(1-Hydroxy-2-methylpropan-2-yl)amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of Int-A6 (1 g, 3.04 mmol, 1.00 equiv),2-amino-2-methylpropan-1-ol dihydrochloride (1.4 g, 8.64 mmol, 3.00equiv), and TEA (924 mg, 9.13 mmol, 3.00 equiv) in DMF (4 mL) wasstirred for 30 min at 60° C. The solvent was concentrated under reducedpressure and the residue was purified by silica gel columnchromatography eluting with EtOAc/petroleum ether (3:7) to afford 700 mg(60%) of title compound as a yellow oil. LCMS: [M+H]⁺ 382.17.

Step 3: Methyl3-(2-methyl-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoate

A solution of5-[(1-hydroxy-2-methylpropan-2-yl)amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(537 mg, 1.41 mmol, 1.00 equiv), methyl prop-2-enoate (1.2 g, 13.9 mmol,10.0 equiv), and Cs₂CO₃ (917 mg, 2.81 mmol, 2.00 equiv) in ACN (10 mL)was stirred for 4 h at RT. The solvent was concentrated under reducedpressure and purified by silica gel column chromatography eluting withEtOAc/petroleum ether (24:76) to afford 320 mg (49%) of the titlecompound as a colorless oil. LCMS: [M+H]⁺ 468.21.

Step 4: Methyl3-(2-methyl-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoate

A solution of methyl3-(2-methyl-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoate(300 mg, 0.64 mmol, 1.00 equiv) and TFA/DCM (12 mL) in DCM (10 mL) wasstirred for 1 h at RT. The resulting mixture was concentrated underreduced pressure to afford 200 mg (92%) of title compound as a yellowoil. LCMS: [M+H]⁺ 338.12.

Step 5:3-(2-Methyl-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoicAcid

A solution of methyl3-(2-methyl-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoate(220 mg, 0.65 mmol, 1.00 equiv) and LiOH.H₂O (42 mg, 1.00 mmol, 1.50equiv) in MeOH/H₂O (4 mL) was stirred overnight at RT. The pH of thesolution was adjusted to 6 with HCl and the resulting mixture wasconcentrated under reduced pressure to afford 200 mg (95%) of titlecompound as a yellow oil which was used directly in the next step. LCMS:[M+H]⁺ 324.11.

Step 6:6-[4-[3-(2-Methyl-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-(2-methyl-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoicacid (200 mg, 0.62 mmol, 1.00 equiv), DIPEA (239 mg, 1.85 mmol, 3.00equiv), HATU (237 mg, 0.62 mmol, 1.01 equiv), and Int-A4 (116 mg, 0.62mmol, 1.00 equiv) in DMF (2 mL) was stirred for 15 min at RT followed bythe addition of three drops of ethanolamine. The residue was purified byC18 reverse phase chromatography eluting with H₂O/ACN to afford 143.4 mg(47%) of title compound as a white solid. LCMS: [M+H]⁺ 494.25. ¹H NMR(400 MHz, DMSO-d₆) δ 8.43 (d, J=2.0 Hz, 1H), 8.10 (s, 1H), 7.78-7.75 (m,1H), 6.88-6.85 (d, J=9.2 Hz, 1H), 3.89-3.86 (m, 2H), 3.83-3.82 (m, 2H),3.74-3.72 (m, 6H), 3.51 (s, 2H), 2.78-2.75 (t, J=6.0 Hz, 2H), 1.48 (s,6H).

Example 520:4-Chloro-5-[2-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)ethoxy]-2,3-dihydropyridazin-3-one

Step 1:4-Chloro-5-[2-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)ethoxy]-2,3-dihydropyridazin-3-one

A solution of Int-A9 (132.05 mg, 0.50 mmol, 1.00 equiv), HATU (229.9 mg,0.60 mmol, 1.20 equiv), DIPEA (195.05 mg, 1.51 mmol, 3.00 equiv), andInt-A2 (140.4 mg, 0.60 mmol, 1.20 equiv) in DMF (3 mL) was stirred for 2h at RT. After concentration, the residue was purified by C18 reversephase chromatography eluting with H₂O/ACN and the residue furtherpurified by Prep-HPLC to afford the title compound as a white solid.LCMS: [M+H]⁺ 477.05. ¹H NMR (300 MHz, Chloroform-d₄) δ 8.53 (s, 2H),7.92 (s, 1H), 4.45 (t, J=4.4 Hz, 2H), 3.95-3.76 (m, 8H), 3.82-3.45 (m,4H), 2.69 (t, J=6.3 Hz, 2H).

The following examples in Table E4 were similarly prepared from Int-A9and the appropriate intermediates according to the method described forExample 520.

TABLE E4 Example Name, structure, analytical data Int. Example 521

Int-A9 and Int-A4 6-[4-(3-[2-[(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoyl)piperazin-1-yl]pyridine-3- carbonitrile; LCMS:[M + H]⁺ 433.05; ¹H NMR (300 MHz, Chloroform-d₄) δ 12.08 (s, 1H), 8.42(d, J = 2.3 Hz, 1H), 7.93 (s, 1H), 7.66 (dd, J = 9.0, 2.4 Hz, 1H), 6.62(d, J = 9.0 Hz, 1H), 4.45 (dd, J = 5.5, 3.2 Hz, 2H), 3.92-3.90 (m, 4H),3.78 (dd, J = 6.5, 3.8 Hz, 4H), 3.72-3.60 (m, 4H), 2.67 (t, J = 6.2 Hz,2H). Example 522*

Int-A9 and Int-A34-Chloro-5-(2-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]ethoxy)-2,3-dihydropyridazin-3-one; LCMS: [M + H]⁺ 443.09; ¹HNMR (300 MHz, DMSO-d6) δ 13.27 (s, 1H), 8.45 (s, 2H), 8.19 (s, 1H), 4.48(t, J = 4.5 Hz, 2H), 3.79-3.65 (m, 8H), 3.55 (s, 4H), 2.63 (t, J = 6.5Hz, 2H). Example 523*

Int-A9 and Int-A54-Chloro-5-(2-[3-[4-(5-chloropyridin-2-yl)piperazin-1-yl]-3-oxopropoxy]ethoxy)-2,3-dihydropyridazin-3-one; LCMS: [M + H]⁺ 442.10; ¹HNMR (400 MHz, DMSO-d6) δ 13.28 (s, 1H), 8.18 (s, 1H), 8.11 (d, J = 2.7Hz, 1H), 7.61 (dd, J = 9.1, 2.7 Hz, lH), 6.87 (d, J = 9.1 Hz, 1H),4.50-4.43 (m, 2H), 3.78-3.69 (m, 4H), 3.58- 3.41 (m, 6H), 3.34 (s, 2H),2.62 (t, J = 6.5 Hz, 2H). *Examples 522 and 523 were made according to asimilar procedure as that of Example 520 but using HOBT (1.5 equiv) andEDCI (1.5 equiv) as coupling reagents.

Example 524:6-(4-[2-[(3-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propyl)amino]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1:6-(4-[2-[(3-Hydroxypropyl)amino]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-[4-(2-chloroacetyl)piperazin-1-yl]pyridine-3-carbonitrile (1.5 g, 5.67mmol, 1 equiv), TEA (1.14 g, 11.27 mmol, 1.99 equiv), and3-aminopropan-1-ol (0.424 g, 5.64 mmol, 1.00 equiv) in EtOH (20 mL) wasstirred for 2 h at RT. The resulting mixture was concentrated underreduced pressure and purified by silica gel column chromatographyeluting with DCM/MeOH (95/5) to afford 1.7 g (99%) of title compound asa yellow oil. LCMS: [M+H]⁺ 304.17.

Step 2: Tert-butylN-[2-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-2-oxoethyl]-N-(3-hydroxypropyl)carbamate

A solution of6-(4-[2-[(3-hydroxypropyl)amino]acetyl]piperazin-1-yl)pyridine-3-carbonitrile(1.7 g, 5.60 mmol, 1 equiv), TEA (1.1 g, 10.87 mmol, 1.94 equiv), and(Boc)₂O (1.5 g, 6.87 mmol, 1.23 equiv) in THF (20 mL) was stirred for 16h at RT. The resulting mixture was concentrated under reduced pressure.The residue was purified by silica gel column chromatography withDCM/MeOH (98/2) to afford 800 mg (35%) of the title compound as a yellowoil. LCMS: [M+H]⁺ 404.22.

Step 3: Tert-butylN-[2-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-2-oxoethyl]-N-(3-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]propyl)carbamate

A solution of tert-butylN-[2-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-2-oxoethyl]-N-(3-hydroxypropyl)carbamate(800 mg, 1.98 mmol, 1 equiv), Cs₂CO₃ (1.3 g, 3.99 mmol, 2.01 equiv), andInt-A6 (977 mg, 2.97 mmol, 1.50 equiv) in ACN (20 mL) was stirred for 16h at RT. The resulting mixture was concentrated under reduced pressureand purified by silica gel column chromatography eluting withEtOAc/petroleum ether (7/3) to afford 280 mg (20%) of title compound asa yellow oil. LCMS: [M+H]⁺ 696.31.

Step 4:6-(4-[2-[(3-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propyl)amino]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of tert-butylN-[2-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-2-oxoethyl]-N-(3-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]propyl)carbamate(280 mg, 0.40 mmol, 1 equiv), and TFA (1 mL) in DCM (10 mL) was stirredfor 2 h at RT. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/ACN followed by furtherpurification by Prep-HPLC to afford the title compound as a white solid(31.7 mg, 17%). LCMS: [M+H]⁺ 466.2. ¹H NMR (300 MHz, DMSO-d6) δ 8.51 (d,J=2.3 Hz, 1H), 8.26 (s, 1H), 7.89 (dd, J=9.1, 2.4 Hz, 1H), 6.94 (d,J=9.0 Hz, 1H), 4.45 (t, J=6.1 Hz, 2H), 3.68 (d, J=5.8 Hz, 4H), 3.42 (s,4H), 3.32 (s, 2H), 2.65 (t, J=6.7 Hz, 2H), 1.87 (q, J=6.4 Hz, 2H).

Example 525:6-[4-[4-(2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)butanoyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1:5-(2-Hydroxyethoxy)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of Int-A6 (5 g, 15.21 mmol, 1 equiv), TEA (3.07 g, 0.03 mmol)and ethane-1,2-diol (945 mg, 15.23 mmol, 1.00 equiv) in ACN (50 mL, 1.22mmol, 0.08 equiv) was stirred for 5 h at 40° C. The solids were filteredand the resulting mixture was concentrated under reduced pressure andpurified by C18 reverse phase chromatography eluting with H₂O/ACN toafford 600 mg (11%) of title compound as a yellow oil. LCMS: [M+H]⁺355.15.

Step 2: Methyl(2E)-4-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]ethoxy)but-2-enoate

A solution of5-(2-hydroxyethoxy)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(510 mg, 1.44 mmol, 1 equiv), methyl (2E)-4-bromobut-2-enoate (1288.0mg, 7.20 mmol, 5.00 equiv), Rockphos (101.2 mg, 0.22 mmol, 0.15 equiv),Cs₂CO₃ (937.7 mg, 2.88 mmol, 2.0 equiv) and Pd₂(allyl)₂Cl₂ (26.3 mg,0.07 mmol, 0.05 equiv) in toluene (12 mL) was stirred for 4 h at 80° C.The solids were filtered and the resulting mixture was concentratedunder reduced pressure and the residue was purified by silica gel columnchromatography eluting with EtOAc/petroleum ether (1:2) to afford 200 mg(31%) of title compound as a yellow oil. LCMS: [M+H]⁺ 453.00.

Step 3: Methyl4-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]ethoxy)butanoate

A solution of methyl(2E)-4-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1-1,6-dihydropyridazin-4-yl]oxy]ethoxy)but-2-enoate(200 mg, 0.44 mmol, 1 equiv) and Pd/C (20 mg, 0.19 mmol, 0.43 equiv) inMeOH (10 mL) under an atmosphere of hydrogen gas was stirred for 1 h atRT. The solids were filtered and the resulting mixture was concentratedunder reduced pressure to afford 160 mg (80%) of title compound as alight yellow solid. LCMS: [M+H]⁺ 455.15.

Step 4: Methyl4-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)butanoate

A solution of methyl4-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]ethoxy)butanoate(200 mg, 0.44 mmol, 1.00 equiv) and trifluoroacetic acid (1 mL) in DCM(5 mL) was stirred for 40 min at RT, and then the resulting mixture wasconcentrated under reduced pressure to afford 170 mg of title compoundas a yellow oil. LCMS: [M+H]⁺ 325.05.

Step 5:4-(2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)butanoicAcid

To a solution of methyl4-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)butanoate(178 mg, 0.55 mmol, 1.00 equiv) in THF (5 mL) was added LiOH (69 mg,2.88 mmol, 3.00 equiv) in water (1 mL). The resulting solution wasstirred for 1 h at RT. HCl (1M) was added to adjust the pH to 4, and theresulting mixture was concentrated under reduced pressure to afford114.0 mg (67%) of title compound as a yellow solid. LCMS: [M+H]⁺ 311.00.

Step 6:6-[4-[4-(2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)butanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of4-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)butanoicacid (70 mg, 0.23 mmol, 1 equiv), HOBT (45.7 mg, 0.34 mmol, 1.50 equiv),EDCI (64.9 mg, 0.34 mmol, 1.50 equiv), and DIPEA (58.3 mg, 0.45 mmol,2.00 equiv) in DMF (5 mL), and Int-A4 (51.0 mg, 0.27 mmol, 1.20 equiv)was added and stirred for 20 min at RT. The resulting solution wasstirred for another 3 h at 60° C. The reaction was then diluted by theaddition of 10 mL of water, extracted with 2×10 mL of EtOAc, washed with1×10 mL of brine and concentrated under reduced pressure. The crudeproduct was purified by C18 reverse phase column chromatography elutingwith H₂O/ACN to afford 33.2 mg (31%) of the title compound as a whitesolid. LCMS: [M+H]⁺ 481.05. ¹H NMR (300 MHz, CD₃OD-d₄) δ 8.46 (dd,J=2.4, 0.8 Hz, 1H), 8.26 (d, J=0.9 Hz, 1H), 7.79 (dd, J=9.1, 2.4 Hz,1H), 6.89 (dd, J=9.1, 0.8 Hz, 1H), 4.59-4.56 (m, 2H), 3.82-3.79 (m, 4H),3.77-3.60 (m, 6H), 3.58 (t, J=6.0 Hz, 2H), 2.50 (dd, J=8.1, 6.9 Hz, 2H),1.97-1.82 (m, 2H).

Example 526:6-[4-[3-(2-[Methyl[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)propyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: 6-[4-(3-Hydroxypropyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of 3-(piperazin-1-yl)propan-1-ol (1 g, 6.93 mmol, 1.00equiv), DIPEA (1.79 g, 13.85 mmol, 2.00 equiv), and6-chloropyridine-3-carbonitrile (958 mg, 6.91 mmol, 1.00 equiv) in NMP(5 mL) was stirred for 1 h at 80° C. The resulting solution wasextracted with 3×30 mL of DC and the organic layers combined andconcentrated under vacuum. After concentration, the residue was purifiedby C18 reverse phase chromatography eluting with H₂O/ACN to afford 1.43g (84%) of title compound as a white solid. LCMS: [M+H]⁺ 247.20.

Step 2: 3-[4-(5-Cyanopyridin-2-yl)piperazin-1-yl]propyl methanesulfonate

A solution of6-[4-(3-hydroxypropyl)piperazin-1-yl]pyridine-3-carbonitrile (1.1 g,4.47 mmol, 1.00 equiv), TEA (904 mg, 8.93 mmol, 2.00 equiv), andmethanesulfonyl methanesulfonate (1.17 g, 6.72 mmol, 1.50 equiv) in DCM(15 mL) was stirred for 3 h at RT. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with DCM/methanol (93:7) to afford 1.02 g (70%) of title compoundas a yellow solid. LCMS: [M+H]⁺ 324.25.

Step 3: Tert-butylN-(2-[3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]propoxy]ethyl)-N-methylcarbamate

To a solution of tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (2.18g, 12.44 mmol, 2.00 equiv) in THF (10 mL) was added sodium hydride (250mg, 6.25 mmol, 2.00 equiv) in several batches at 0° C. The mixture wasstirred for 10 min and then3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]propyl methanesulfonate (1.02g, 3.14 mmol, 1.00 equiv) was added. The resulting solution was stirredfor 2 h at RT. The reaction was then quenched by the addition of 15 mLof water. The resulting solution was extracted with 3×30 mL of EtOAc andthe organic layers combined. After concentration, the residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(7:3) to afford 1.6 g of title compound as a yellow oil. LCMS: [M+H]⁺404.25.

Step 4:6-(4-[3-[2-(Methylamino)ethoxy]propyl]piperazin-1-yl)pyridine-3-carbonitrilehydrochloride

A solution of tert-butylN-(2-[3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]propoxy]ethyl)-N-methylcarbamate(500 mg, 1.24 mmol, 1.00 equiv) in HCl/dioxane (5 mL) was was stirredfor 30 min at RT. The resulting mixture was concentrated under vacuum toafford 500 mg of title compound as a yellow solid. LCMS: [M+H]⁺ 304.25.

Step 5:6-[4-[3-(2-[Methyl[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)propyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-(4-[3-[2-(methylamino)ethoxy]propyl]piperazin-1-yl)pyridine-3-carbonitrilehydrochloride (400 mg, 1.18 mmol, 1 equiv), TEA (238.2 mg, 2.35 mmol, 2equiv), and Int-A6 (387.0 mg, 1.18 mmol, 1 equiv) in EtOH (10 mL) wasstirred for 5 h at RT. The resulting mixture was concentrated underreduced pressure and purified by silica gel column chromatographyeluting with DCM/MeOH (93/7) to afford 500 mg (71%) of title compound asa yellow oil. LCMS: [M+H]⁺ 596.29.

Step 6:6-[4-[3-(2-[Methyl[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)propyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-[3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)propyl]piperazin-1-yl]pyridine-3-carbonitrile(490 mg, 0.82 mmol, 1 equiv) in DCM (10 mL) and TFA (1 mL) was stirredfor 2 h at RT. The reaction was then quenched by the addition of 10 mLof water and the resulting solution was extracted with 3×30 mL of DCMand the organic layers combined and concentrated under reduced pressure.The residue was purified by C18 reverse phase chromatography elutingwith H₂O/ACN and further purified by Prep-HPLC to afford the titlecompound as a white solid (71.7 mg, 19%). LCMS: [M+H]⁺ 466.21. ¹H NMR(300 MHz, DMSO-d6) δ 8.48 (d, J=2.4 Hz, 1H), 8.02 (s, 1H), 7.85 (dd,J=9.1, 2.4 Hz, 1H), 6.93 (d, J=9.2 Hz, 1H), 3.60 (m, 8H), 3.41 (t, J=6.3Hz, 2H), 3.05 (d, J=2.5 Hz, 3H), 2.37 (t, J=5.1 Hz, 4H), 2.26 (t, J=7.4Hz, 2H), 1.62 (s, 2H).

Example 527 Isomer A:6-(4-[3-[(2S)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2-(pyridin-4-yl)ethoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 527 Isomer B:6-(4-[3-[(2R)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2-(pyridin-4-yl)ethoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1:5-[[2-Hydroxy-1-(pyridin-4-yl)ethyl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of 2-amino-2-(pyridin-4-yl)ethan-1-ol (1 g, 7.24 mmol, 1.00equiv), TEA (2.93 g, 28.96 mmol, 4.00 equiv), Int-A6 (2.85 g, 8.67 mmol,1.20 equiv) in EtOH (21 mL) was stirred for 1 h at 60° C. The resultingmixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography eluting withEtOAc/petroleum ether (2/1) to afford 1 g (32%) of title compound as ayellow oil. LCMS: [M+H]⁺ 431.17.

Step 2: Methyl3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]-2-(pyridin-4-yl)ethoxy)propanoate

A solution of5-[[2-hydroxy-1-(pyridin-4-yl)ethyl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(730 mg, 1.70 mmol, 1.00 equiv), methyl prop-2-enoate (1.46 g, 16.96mmol, 10.00 equiv), and Cs₂CO₃ (1.1 g, 3.38 mmol, 2.00 equiv) in DMF (15mL) was stirred for 6 h at RT. The resulting solution was quenched by 50mL of water and was extracted with EtOAc (3×50 mL), and then the organiclayers combined. The solution was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography with EtOAc/petroleum ether (1:2) toafford 400 mg (46%) of title compound as a yellow oil. LCMS: [M+H]⁺517.21.

Step 3: Methyl3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2-(pyridin-4-yl)ethoxy)propanoate

A solution of methyl3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]-2-(pyridin-4-yl)ethoxy)propanoate(370 mg, 0.72 mmol, 1.00 equiv) in DCM/TFA (18 mL) was stirred 0.5 h atRT. The resulting mixture was concentrated under reduced pressure toafford 278 mg title compound as a yellow oil. LCMS: [M+H]⁺ 387.13.

Step 4: Methyl3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2-(pyridin-4-yl)ethoxy)propanoicAcid

A solution of methyl3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2-(pyridin-4-yl)ethoxy)propanoate(278 mg, 0.72 mmol, 1.00 equiv), LiOH (52 mg, 2.17 mmol, 3.00 equiv),and water (4.5 mL) in MeOH (4.5 mL) was stirred for 6 h at RT. The pH ofthe solution was adjusted to 5 with HCl. The resulting mixture wasconcentrated under reduced pressure to afford 260 mg title compound as acrude yellow oil. LCMS: [M+H]⁺ 373.11.

Step 5:6-(4-[3-[(2S)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2-(pyridin-4-yl)ethoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrileand6-(4-[3-[(2R)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2-(pyridin-4-yl)ethoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2-(pyridin-4-yl)ethoxy)propanoicacid (260 mg, 0.70 mmol, 1.00 equiv), HATU (319 mg, 0.84 mmol, 1.20equiv), DIPEA (0.5 mL, 2.00 equiv), and Int-A4 (130 mg, 0.69 mmol, 1.00equiv) in DMF (5 mL) was stirred for 1 h at RT. After concentration, theresidue was purified by C18 reverse phase chromatography eluting withH₂O/ACN followed by further purification by Prep-HPLC. The enantiomerswere separated by Chiral-Prep-HPLC (Repaired Chiral IA, 5 μm, 0.46×10 cmcolumn, eluting with a gradient of MtBE (1% DEA):EtOH=70:30, at a flowrate of 1 mL/min) to afford the title compounds as white solids. Theabsolute stereochemistry was assigned in analogy to Example 513A, basedon the PARP7 potency of the more potent enantiomer and in analogy to theExample 513A X-ray.

Example 527 Isomer A

31.2 mg, 8%, LCMS: [M+H]⁺ 543.21. ¹H NMR (300 MHz, Methanol-d4) δ 8.56(d, J=3.3 Hz, 2H), 8.44 (dd, J=2.4, 0.7 Hz, 1H), 7.78 (dd, J=9.1, 2.4Hz, 1H), 7.58 (s, 1H), 7.47 (dd, J=4.8, 1.5 Hz, 1H), 6.86 (dd, J=9.1,0.8 Hz, 1H), 5.20 (m, 1H), 4.00-3.73 (m, 6H), 3.71-3.64 (m, 6H),2.77-2.66 (m, 2H). tR=2.156 min.

Example 527 Isomer B

27.3 mg, 8%, LCMS: [M+H]⁺ 543.21. tR=6.396 min.

Example 528 Isomer A:(S)-6-(4-(3-(3-Methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazin-1-yl)nicotinonitrileand Example 528 Isomer B:(R)-6-(4-(3-(3-Methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazin-1-yl)nicotinonitrile

Step 1: Tert-butyl 3-(2-[[(tert-butoxy)carbonyl]amino]ethoxy)butanoate

A solution of tert-butyl N-(2-hydroxyethyl)carbamate (3.2 g, 19.85 mmol,1.00 equiv), Cs₂CO₃ (1.5 g, 4.60 mmol, 2.00 equiv),(Z)-tert-butylbut-2-enoate (28 g, 196.9 mmol, 10.00 equiv) in ACN (20mL) was stirred for 1 overnight at 25° C. The resulting mixture wasconcentrated under reduced pressure and purified by silica gel columnchromatography eluting with EtOAc/petroleum ether (1:4) to afford 420 mg(7%) of title compound as a colorless oil. LCMS: [M+H]⁺ 304.39.

Step 2: 3-(2-Aminoethoxy)butanoic Acid

A solution of tert-butyl3-(2-[[(tert-butoxy)carbonyl]amino]ethoxy)butanoate (420 mg, 1.38 mmol,1.00 equiv), a solution of HCl/dioxane (15 mL) in dioxane (15 mL) wasstirred overnight at 25° C. The resulting mixture was concentrated underreduced pressure to afford 200 mg (98%) of title compound as a yellowoil. LCMS: [M+H]⁺ 148.18.

Step 3:3-(2-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)butanoicAcid

A solution of Int-A6 (400 mg, 1.22 mmol, 1.00 equiv), TEA (369 mg, 3.65mmol, 3.00 equiv), EtOH (12 mL), and 3-(2-aminoethoxy)butanoic acid (180mg, 1.22 mmol, 1.00 equiv) in EtOH (12 mL) was stirred for 40 min at 60°C. The resulting mixture was concentrated under reduced pressure toafford 500 mg (94%) of title compound as a yellow oil. LCMS: [M+H]⁺440.18.

Step 4:6-[4-[3-(2-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)butanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)butanoicacid (500 mg, 1.14 mmol, 1.00 equiv), HATU (430 mg, 1.13 mmol, 1.01equiv), DIPEA (294 mg, 2.27 mmol, 2.00 equiv), Int-A4 (200 mg, 1.06mmol, 1.00 equiv) in DMF (3 mL) was stirred for 30 min at 25° C. Afterconcentration under reduced pressure, the residue was purified by C18reverse phase chromatography eluting with H₂O/ACN to afford 300 mg (43%)of title compound as a yellow oil. LCMS: [M+H]⁺ 610.20.

Step 5:(S)-6-[4-[3-(2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)butanoyl]piperazin-1-yl]pyridine-3-carbonitrileand(R)-6-[4-[3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)butanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-[3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)butanoyl]piperazin-1-yl]pyridine-3-carbonitrile(300 mg, 0.49 mmol, 1.00 equiv), and a solution of TFA/DCM (12 mL) inDCM (10 mL) was stirred for 30 min at 25° C. After concentration, theresidue was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN. The residue was further purified by Prep-HPLC andChiral-Prep-HPLC (Chiralpak IA, 5 μm, 2×25 cm column, eluting with agradient of Hexanes (0.1% DEA):EtOH=50:50, at a flow rate of 1 mL/min)to afford (after arbitrary assignment of stereoisomers) the titlecompounds as white solids.

Example 528 Isomer A

61.7 mg, 32%, LCMS: [M+H]⁺ 480.15. ¹H NMR (400 MHz, DMSO-d₆) δ 12.41 (s,1H), 8.51 (d, J=2.3 Hz, 1H), 7.89-7.86 (dd, J=2.0, 8.8 Hz, 2H),6.94-6.92 (d, J=9.1 Hz, 1H), 6.83-6.82 (s, 1H), 3.92-3.84 (m, 1H),3.69-3.51 (m, 12H), 2.67-2.60 (dd, J=15.7, 7.2 Hz, 1H), 2.39-2.35 (dd,J=15.7, 5.1 Hz, 1H), 1.12 (d, J=6.1 Hz, 3H). tR=1.03.

Example 528 Isomer B

57.9 mg, 30%, LCMS: [M+H]⁺ 480.15. tR=1.04 min.

Example 529:6-[4-[3-(3-Hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Tert-butyl4-(hydroxymethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

A solution of 3-tert-butyl 4-methyl2,2-dimethyl-1,3-oxazolidine-3,4-dicarboxylate (5 g, 19.28 mmol, 1.00equiv) and CaCl₂ (4.28 g, 2.00 equiv) in THF (100 mL) and MeOH (20 mL),followed by NaBH₄ (1.46 g, 38.59 mmol, 2.00 equiv) was added and stirredfor 4 h at RT. The resulting solution was stirred for another 30 min atRT. The reaction was quenched by the addition of 20 mL of water,extracted with 3×100 mL of EtOAc, dried over anhydrous sodium sulfateand concentrated under reduced pressure to afford 4.3 g (96%) of titlecompound as a yellow oil. LCMS: [M+H]⁺ 232.15.

Step 2: Tert-butyl4-[(3-methoxy-3-oxopropoxy)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

To a solution of tert-butyl4-(hydroxymethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1 g, 4.32mmol, 1.00 equiv) and Cs₂CO₃ (2.81 g, 8.62 mmol, 2.00 equiv) in ACN (25mL) was added methyl prop-2-enoate (1.88 g, 21.84 mmol, 5.00 equiv)dropwise. The reaction mixture was stirred for 20 min at RT and theresulting solution was stirred for another 3 h at RT. The solids werefiltered and the residue was concentrated under reduced pressure toafford 1.1 g (80%) of title compound as a yellow oil. LCMS: [M+H]⁺318.18.

Step 3: Methyl 3-((2,2-dimethyloxazolidin-4-yl)methoxy)propanoate

A solution of tert-butyl4-[(3-methoxy-3-oxopropoxy)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(1 g, 3.12 mmol, 1.00 equiv) in HCl/dioxane (10 mL, 4M) was stirred for40 min at RT, and the residue was then concentrated under reducedpressure to afford 920 mg of title compound as a brown oil. LCMS: [M+H]⁺218.18.

Step 4: Methyl3-(3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoate

A solution of methyl3-[(2,2-dimethyl-1,3-oxazolidin-4-yl)methoxy]propanoate (1.29 g, 5.94mmol, 1.00 equiv), DIPEA (1.01 g, 7.81 mmol, 2.00 equiv) and Int-A6 (860mg, 2.62 mmol, 1.00 equiv) in IPA (10 mL) was stirred for 1 h at 60° C.The resulting mixture was concentrated under reduced pressure and theresidue was purified by silica gel column chromatography eluting withEtOAc/petroleum ether (2:3) to afford 570 mg (20%) of title compound asa yellow oil. LCMS: [M+H]⁺ 470.10.

Step 5: Methyl3-(3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoate

A solution of methyl3-(3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoate(550 mg, 1.17 mmol, 1.00 equiv) and TFA (2 mL) in DCM (10 mL) wasstirred for 40 min at RT, and then concentrated under reduced pressureto afford 500 mg of title compound as a yellow oil. LCMS: [M+H]⁺ 340.00.

Step 6:3-(3-Hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoicAcid

A solution of methyl3-(3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoate(550 mg, 1.62 mmol, 1.00 equiv) and LiOH.H₂O (203 mg, 4.84 mmol, 3.00equiv) in water (3 mL) and THF (15 mL) was stirred for 2 h at RT, andthen diluted with 5 mL of water, extracted with 10 mL of EtOAc and theaqueous layers combined. The aqueous layers were adjusted to pH 4 andconcentrated under reduced pressure to afford 300 mg (57%, containingsome lithium chloride) of crude title compound as a yellow solid. LCMS:[M+H]⁺ 326.09.

Step 7:6-[4-[3-(3-Hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-(3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoicacid (105 mg, 0.32 mmol, 1 equiv), HOBT (65.4 mg, 0.48 mmol, 1.5 equiv),EDCI (92.8 mg, 0.48 mmol, 1.5 equiv), DIPEA (83.4 mg, 0.65 mmol, 2.0equiv) and Int-A4 (72.9 mg, 0.39 mmol, 1.20 equiv) in DMF (10 mL) wasstirred for 3 h at RT followed by washing with 1×20 mL of H₂O, andextraction with 3×20 mL of EtOAc. The organic layer was combined, washedwith 1×20 mL of brine and concentrated under reduced pressure. Theresidue was purified by C18 reverse phase chromatography eluting withH₂O/ACN to afford 11.3 mg (7%) of title compound as a white solid. LCMS:[M+H]⁺ 496.10. ¹H NMR (300 MHz, DMSO-d₆) δ 12.32-12.89 (br, 1H), 8.51(s, 1H), 7.94-7.84 (m, 2H), 6.94 (d, J=9.0 Hz, 1H), 6.25 (dd, J=8.8, 4.5Hz, 1H), 5.08 (t, J=5.4 Hz, 1H), 4.06 (s, 1H), 3.73-3.62 (m, 6H),3.55-3.50 (m, 8H), 2.64-2.51 (t, J=6.4 Hz, 2H).

Example 530 Isomer A:6-(4-[3-[(2S)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 530 Isomer B:6-(4-[3-[(2R)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 530 Isomer C:6-[4-(3-[[(2S)-1-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propan-2-yl]oxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrileand Example 530 Isomer D:6-[4-(3-[[(2R)-1-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propan-2-yl]oxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1: Mixture of6-[4-[3-(2-hydroxypropoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrileand6-(4-(3-(1-hydroxypropan-2-yloxy)propanoyl)piperazin-1-yl)nicotinonitrile

A solution of propane-1,2-diol (1.9 g, 25.0 mmol, 5.00 equiv), Cs₂CO₃(3.25 g, 10.0 mmol, 2.00 equiv), and Int-A25 (1.21 g, 4.99 mmol, 1.00equiv) in ACN (25 mL) was stirred for 5 h at 60° C. After concentrationunder reduced pressure, the residue was purified by C18 reverse phasechromatography eluting with H₂O/ACN to afford 1.25 g (76%) of a mixtureof the title compounds as white oils. LCMS: [M+H]⁺ 319.18.

Step 2: Mixture of6-[4-[3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]propoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrileand6-(4-(3-(1-(6-oxo-5-(trifluoromethyl)-((2-(triethylsilyl)ethoxy)ethyl)-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yloxy)propan-2-yloxy)propanoyl)piperazin-1-yl)nicotinonitrile

A solution of the mixture of6-[4-[3-(2-hydroxypropoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrileand 6-(4-(3-(1-(6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yloxy)propan-2-yloxy)propanoyl)piperazin-1-yl)nicotinonitrile(1.25 g, 3.93 mmol, 1.00 equiv), Cs₂CO₃ (1.9 g, 5.83 mmol, 1.50 equiv),and Int-A6 (1.55 g, 4.71 mmol, 1.20 equiv) in DMF (20 mL) was stirredfor 6 h at 80° C. The solids were filtered and the resulting solutionwas quenched by water (30 mL) and extracted with EtOAc (3×30 mL) and theorganic layers combined. The solution was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography with EtOAc/petroleum ether(1:1) to afford 1.2 g (50%) of the mixture of the title compounds as ayellow oil. LCMS: [M+H]⁺ 611.26.

Step 3: Synthesis of6-(4-[3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile,6-(4-[3-[(2R)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile,6-[4-(3-[[(2S)-1-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propan-2-yl]oxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrileand6-[4-(3-[[(2R)-1-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propan-2-yl]oxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-[3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrileand6-(4-(3-(1-(6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yloxy)propan-2-yloxy)propanoyl)piperazin-1-yl)nicotinonitrilemixture (260 mg, 0.54 mmol, 1.00 equiv) in TFA/DCM (30 mL) was stirredfor 1 h at RT. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/ACN. The residue wasfurther purified by Prep-HPLC and Chiral-Prep-HPLC to separate outisomers A and B (CHIRALPAK IF-3, 3 rpm, 0.46×5 cm column, eluting with agradient of hexanes (0.1% DEA):DCM=50:50, at a flow rate of 1 mL/min)and isomers C and D (CHIRALPAK IC-3, 3 μm, 0.46×5 cm column, elutingwith hexanes:DCM (3:1) (0.1% DEA):EtOH=50:50, at a flow rate of 1mL/min) to afford the title compounds as white solids. The twoenantiomers isomers A and B absolute stereochemistry was assigned inanalogy to Example 513A, based on the PARP7 potency of the more potentenantiomer and in analogy to the Example 513A X-ray. The stereochemistryof isomers C and D was arbitrarily assigned. The position of the methylgroup was confirmed by ¹H-NMR.

Example 530 Isomer A

54.3 mg, 21%, LCMS: [M+H]⁺ 481.15. ¹H NMR (300 MHz, Methanol-d₄) δ 8.41(s, 1H), 8.21 (s, 1H), 7.75 (dd, J=9.1, 2.3 Hz, 1H), 6.83 (dd, J=9.1,0.8 Hz, 1H), 5.14-5.08 (m, 1H), 3.85-3.54 (m, 12H), 2.63 (t, J=5.9 Hz,2H), 1.34 (d, J=6.3 Hz, 3H). tR=1.453 min.

Example 530 Isomer B

59.7 mg, 23%, LCMS: [M+H]⁺ 481.10, tR=2.988 min.

Example 530 Isomer C

18.2 mg, 7%, LCMS: [M+H]⁺ 481.10. ¹H NMR (300 MHz, Methanol-d₄) δ 8.41(d, J=1.8 Hz, 1H), 8.19 (s, 1H), 7.74 (dd, J=9.1, 2.4 Hz, 1H), 6.83 (dd,J=9.1, 0.8 Hz, 1H), 4.41-4.32 (m, 2H), 3.93-3.85 (m, 2H), 3.84-3.76 (m,3H), 3.75-3.65 (m, 6H), 2.65 (t, J=6.0 Hz, 2H), 1.24 (d, J=6.4 Hz, 3H).tR=2.331 min.

Example 530 Isomer D

38.2 mg, 15%, LCMS: [M+H]⁺ 481.15. tR=2.810 min.

Example 531:6-[4-(3-[[(3R,4S)-4-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]oxolan-3-yl]oxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1:6-(4-(3-((3R,4S)-4-Hydroxy-tetrahydrofuran-3-yloxy)propanoyl)piperazin-1-yl)nicotinonitrile

A solution of (3S,4R)-tetrahydrofuran-3,4-diol (1 g, 9.61 mmol, 1equiv), Cs₂CO₃ (6.3 g, 19.2 mmol, 2 equiv),6-[4-(prop-2-enoyl)piperazin-1-yl]pyridine-3-carbonitrile (2.3 g, 9.6mmol, 1 equiv) in ACN (20 mL) was stirred for 5 h at 60° C. The solventwas concentrated under reduced pressure and the residue was purified bysilica gel column chromatography eluting with DCM/MeOH (99/1) to afford100 mg (3%) of title compound as a white oil. LCMS: [M+H]⁺ 347.16.

Step 2:6-(4-(3-((3R,4S)-4-(6-Oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yloxy)-tetrahydrofuran-3-yloxy)propanoyl)piperazin-1-yl)nicotinonitrile

A solution of6-(4-(3-((3R,4S)-4-hydroxy-tetrahydrofuran-3-yloxy)propanoyl)piperazin-1-yl)nicotinonitrile(100 mg, 0.28 mmol, 1 equiv), Cs₂CO₃ (188 mg, 0.56 mmol, 2 equiv),Int-A6 (475 mg, 0.14 mmol, 5 equiv) in ACN (20 mL) was stirred for 1 dayat RT. The resulting mixture was concentrated under reduced pressure andthe residue was purified by silica gel column chromatography elutingwith DCM/MeOH (95/5) to afford 50 mg (28%) of title compound as a whiteoil. LCMS: [M+H]⁺ 639.25.

Step 3:6-[4-(3-[[(3R,4S)-4-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]oxolan-3-yl]oxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-(4-(3-((3R,4S)-4-(6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yloxy)-tetrahydrofuran-3-yloxy)propanoyl)piperazin-1-yl)nicotinonitrile(50 mg, 0.078 mmol, 1 equiv), TFA (1 mL, 13.5 mmol, 43.0 equiv) in DCM(10 mL) was stirred for 1 h at RT. The solvent was concentrated underreduced pressure and the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN. Then the residue was furtherpurified by Prep-HPLC to afford the title compound (16.6 mg, 43%) as awhite solid. LCMS: [M+H]⁺ 509.2. ¹H NMR (300 MHz, DMSO-d6) δ 8.52 (d,J=2.3 Hz, 1H), 8.29 (s, 1H), 7.89 (dd, J=9.1, 2.3 Hz, 1H), 6.94 (d,J=9.1 Hz, 1H), 5.50 (s, 1H), 4.35 (q, J=6.1 Hz, 1H), 4.03 (dd, J=10.8,4.7 Hz, 1H), 3.98-3.82 (m, 2H), 3.69-3.52 (m, 7H), 3.50-3.48 (m, 4H),2.46 (m, 2H).

Example 532 Isomer A:6-(4-[3-[(2S)-3-Methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 532 Isomer B:6-(4-[3-[(2R)-3-Methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1:6-[4-[3-(2-Hydroxy-3-methoxypropoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of Int-A25 (1.3 g, 5.37 mmol, 1.00 equiv), Cs₂CO₃ (3.49 g,10.71 mmol, 2.00 equiv), and 3-methoxypropane-1,2-diol (2.28 g, 21.48mmol, 4.00 equiv) in ACN (30 mL) was stirred for 5 h at 70° C. Thesolvent was concentrated under reduced pressure and the residue waspurified by silica gel column chromatography with chloroform/MeOH (1:10)to afford 1.41 g (75%) of title compound as a white oil. LCMS: [M+H]⁺349.00.

Step 2:6-[4-[3-(3-Methoxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]propoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-[3-(2-hydroxy-3-methoxypropoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile(1.29 g, 3.70 mmol, 1.00 equiv), Cs₂CO₃ (1.8 g, 5.52 mmol, 1.50 equiv),and Int-A6 (1.46 g, 4.44 mmol, 1.20 equiv) in ACN (30 mL) was stirredfor 8 h at 80° C. The resulting mixture was concentrated under reducedpressure and the residue was applied onto a silica gel column withEtOAc/petroleum ether (1:1) to afford 1.58 g (67%) of title compound asa brown oil. LCMS: [M+H]⁺ 641.00.

Step 6:6-(4-[3-[(2S)-3-Methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrileand6-(4-[3-[(2R)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-[4-[3-(3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy)propanoyl]piperazin-1-yl]pyridine-3-carbonitrile(1.56 g, 3.06 mmol, 1 equiv), TFA (6 mL) in DCM (30 mL) was stirred for40 min at RT. After concentration under reduced pressure, the residuewas further purified by Prep-HPLC and Chiral-Prep-HPLC (CHIRALPAK ID-3,3 μm, 0.46×10 cm column, eluting with MTBE (0.1% DEA):EtOH=70:30, at aflow rate of 1 mL/min) yielding the title compounds as white solids. Theabsolute stereochemistry was assigned in analogy to Example 513A, basedon the PARP7 potency of the more potent enantiomer and in analogy to theExample 513A X-ray.

Example 532 Isomer A

21.7 mg, LCMS: [M+H]⁺ 511.05. ¹H NMR (300 MHz, Chloroform-d4) δ 11.22(s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.06 (s, 1H), 7.68 (dd, J=9.0, 2.4 Hz,1H), 6.64 (d, J=9.0 Hz, 1H), 4.89-4.82 (m, 1H), 3.94-3.90 (m, 1H),3.89-3.71 (m, 7H), 3.71-3.64 (m, 2H), 3.64-3.55 (m, 4H), 3.39 (s, 3H),2.69-2.51 (m, 2H). tR=1.935 min

Example 532 Isomer B

40.5 mg, LCMS [M+H]⁺ 511.05. tR=2.359 min.

Example 533:5-(2-[3-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]ethoxy)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of Int-A11 (50 mg, 0.17 mmol, 1 equiv), DIPEA (65.5 mg, 0.51mmol, 3 equiv), HOBT (34.2 mg, 0.25 mmol, 1.5 equiv), EDCI (48.5 mg,0.25 mmol, 1.5 equiv), and Int-A3 (43.7 mg, 0.19 mmol, 1.1 equiv) in DMF(1.5 mL) was stirred for 4 h at RT. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN andthe residue was further purified by Prep-HPLC to afford the titlecompound as a white solid (21 mg, 26%). LCMS [M+H]⁺ 477.12. ¹H NMR (300MHz, DMSO-d6) δ 8.45 (s, 2H), 8.25 (s, 1H), 4.53 (s, 2H), 3.74-3.69 (m,8H), 3.54 (d, J=5.6 Hz, 4H), 2.61 (t, J=6.5 Hz, 2H).

The following examples in Table E5 were similarly prepared according tothe method described for Example 533.

TABLE E5 Example Name, structure, analytical data Int. Example 534

Int-A2 and Int-A115-[2-(3-Oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)ethoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one; LCMS:[M + H]⁺ 511.15; ¹H NMR (300 MHz, DMSO-d6) δ 13.28 (s, 1H), 8.72 (d, J =0.6 Hz, 2H), 8.26-8.19 (m, 1H), 4.50 (t, J = 4.4 Hz, 2H), 3.86- 3.63 (m,4H), 3.72 (m, 4H), 3.56 (m, 4H), 2.59 (t, J = 6.5 Hz, 2H). Example 535

Int-A5 and Int-A11 5-(2-[3-[4-(5-Chloropyridin-2-yl)piperazin-1-yl]-3-oxopropoxy]ethoxy)-4-(trifluoromethyl)-2,3-dihydropyridazin- 3-one;LCMS: [M + H]⁺ 476.12; ¹H NMR (300 MHz, DMSO-d6) δ 13.30 (s, 1H), 8.25(s, 1H), 8.13 (d, J = 2.7 Hz, 1H), 7.62 (dd, J = 9.1, 2.7 Hz, 1H), 6.88(d, J = 9.0 Hz, 1H), 4.52 (d, J = 4.8 Hz, 2H), 3.71 (t, J = 6.3 Hz, 4H),3.48 (m, 8H), 2.61 (t, J = 6.5 Hz, 2H). Example 536

Int-A11 and Int-A185-[2-(3-Oxo-3-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]propoxy)ethoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin- 3-one;LCMS: [M + H]⁺ 510.15; ¹H NMR (300 MHz, DMSO-d6) δ 13.27 (s, 1H), 8.40(s, 1H), 8.22 (s, 1H), 7.80 (dd, J = 9.1, 2.6 Hz, 1H), 6.93 (d, J = 9.2Hz, 1H), 4.50 (t, J = 4.4 Hz, 2H), 3.67-3.30 (m, 12H), 2.58 (t, J = 6.5Hz, 2H).

Example 537 Isomer A:6-[4-(3-[[(1S,2S)-1-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]-2,3-dihydro-1H-inden-2-yl]oxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrileand Example 537 Isomer B:6-[4-(3-[[(1R,2R)-1-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]-2,3-dihydro-1H-inden-2-yl]oxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1:5-[(2-Hydroxy-2,3-dihydro-1H-inden-1-yl)amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of Int-A6 (2.00 equiv), 1-amino-2,3-dihydro-1H-inden-2-ol(226 mg, 1.51 mmol, 1.00 equiv), and TEA (308 mg, 3.04 mmol, 2.00 equiv)in ethanol (12 mL) was stirred for 1 h at 60° C. The resulting solutionwas concentrated under vacuum and then the residue was applied onto asilica gel column eluting with EtOAc/petroleum ether (35:65) to afford356 mg (53%) of the title compound as a light yellow solid. LCMS [M+H]⁺.

Step 2: Methyl3-[(1-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]-2,3-dihydro-1H-inden-2-yl)oxy]propanoate

A solution of5-[(2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(340 mg, 0.77 mmol, 1.00 equiv), Cs₂CO₃ (752 mg, 2.31 mmol, 3.00 equiv)and methyl prop-2-enoate (200 mg, 2.32 mmol, 3.00 equiv) in ACN (10 mL)was stirred for 3 days at RT, and then the resulting solution wasdiluted with 80 mL of EtOAc, washed with 3×50 mL of H₂O, and the organiclayers were combined and dried over anhydrous sodium sulfate. Afterconcentration under reduced pressure, the residue was purified by silicagel column chromatography eluting with EtOAc/petroleum ether (35:65) toafford 152 mg (37%) of title compound as a brown oil. LCMS [M+H]⁺528.21.

Step 3: Methyl3-[(1-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2,3-dihydro-1H-inden-2-yl)oxy]propanoateTFA salt

A solution of methyl 3-[(1-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]-2,3-dihydro-1H-inden-2-yl)oxy]propanoate(147 mg, 0.28 mmol, 1.00 equiv) and TFA (1 mL) in DCM (4 mL) was stirredfor 1 h at RT, and then the resulting mixture was concentrated undervacuum to afford 115 mg (83%) of title compound as a light brown oil.LCMS [M+H]⁺ 398.12.

Step 4:3-[(1-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2,3-dihydro-1H-inden-2-yl)oxy]propanoicAcid

A solution of methyl3-[(1-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2,3-dihydro-1H-inden-2-yl)oxy]propanoateTFA salt (115 mg, 0.29 mmol, 1.00 equiv) and LiOH.H₂O (122 mg, 10.00equiv) in MeOH (2.5 mL) and water (0.5 mL) was stirred for 1 h at 30°C., and then the pH value of the solution was adjusted to 4 with HCl(36.5%), and then the resulting mixture was concentrated under vacuum toafford 110 mg (99%, crude product, mixed with LiCl) of title compound asa light yellow solid. LCMS [M+H]⁺ 384.11.

Step 5:6-[4-(3-[[(1S,2S)-1-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]-2,3-dihydro-1H-inden-2-yl]oxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrileand6-[4-(3-[[(1R,2R)-1-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]-2,3-dihydro-1H-inden-2-yl]oxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-[(1-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]-2,3-dihydro-1H-inden-2-yl)oxy]propanoicacid (110 mg, 0.29 mmol, 1.00 equiv), HATU (87 mg, 0.23 mmol, 0.80equiv), DIPEA (74 mg, 0.57 mmol, 2.00 equiv) and Int-A4 (53.7 mg, 0.29mmol, 1.00 equiv) in DMF (2.5 mL) was stirred for 2 h at RT, then theresidue was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN, and then the residue was further purified by Prep-HPLC andChiral-Prep-HPLC (CHIRAL Repaired IC, 5 μm, 0.46×10 cm column, elutingwith MTBE (0.1% DEA):EtOH=70:30, at a flow rate of 1 mL/min) yieldingthe title compounds. The absolute stereochemistry was assigned inanalogy to Example 513A, based on the PARP7 potency of the more potentenantiomer and in analogy to the Example 513A X-ray.

Example 537 Isomer A

5.9 mg, 19%, LCMS [M+H]⁺ 554.15. ¹H NMR (300 MHz, Methanol-d₄) δ 8.40(s, 1H), 8.10 (s, 1H), 7.76 (dd, J=9.1, 2.4 Hz, 1H), 7.28 (d, J=7.2 Hz,1H), 7.16-7.13 (m, 2H), 7.09 (d, J=7.2 Hz, 1H), 6.77 (d, J=8.7 Hz, 1H),5.46 (d, J=4.5 Hz, 1H), 4.85 (d, J=6.9 Hz, 1H), 4.47-4.42 (m, 1H),3.94-3.91 (m, 1H), 3.84-3.67 (m, 4H), 3.53-3.44 (m, 3H), 3.29-3.09 (m,3H), 2.81-2.73 (m, 1H), 2.60-2.49 (m, 1H). tR=2.583 min.

Example 537 Isomer B

4.9 mg, 16%, LCMS [M+H]⁺ 554.15. tR=3.468 min.

Example 538 Isomer A:6-[4-[(3R)-3-(2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)butanoyl]piperazin-1-yl]pyridine-3-carbonitrileand Example 538 Isomer B:6-[4-[(3S)-3-(2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)butanoyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: 6-[4-[(2E)-But-2-enoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of (2E)-but-2-enoyl (2E)-but-2-enoate (1.05 g, 6.81 mmol,1.30 equiv), TEA (1.5 g, 15.0 mmol, 3.00 equiv), and Int-A4 (1 g, 5.31mmol, 1.00 equiv) in DCM (20 mL) was stirred for 1 h at RT. The solventwas concentrated under vacuum and the residue was purified by silica gelcolumn chromatography eluting with EtOAc/petroleum ether (1:1) to afford1.28 g (94%) of title compound as a white solid. LCMS [M+H]⁺ 257.00.

Step 2:6-[4-[3-(2-Hydroxyethoxy)butanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-[(2E)-but-2-enoyl]piperazin-1-yl]pyridine-3-carbonitrile (1.3 g,4.93 mmol, 1.00 equiv), Cs₂CO₃ (3.2 g, 9.82 mmol, 2.00 equiv), andethane-1,2-diol (1.5 g, 24.2 mmol, 5.00 equiv) in ACN (30 mL) wasstirred for 2 days at 75° C. The solvent was concentrated under vacuumand the residue was purified by silica gel column chromatography elutingwith chloroform/MeOH (1:10) to afford 1.01 g (64%) of title compound asa white solid. LCMS [M+H]⁺ 319.

Step 3:6-[4-[3-(2-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]ethoxy)butanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-[3-(2-hydroxyethoxy)butanoyl]piperazin-1-yl]pyridine-3-carbonitrile(818 mg, 2.57 mmol, 1.00 equiv), Cs₂CO₃ (1 g, 3.07 mmol, 1.20 equiv),and Int-A6 (2.5 g, 7.60 mmol, 3.00 equiv) in DMF (20 mL) was stirred for5 h at 80° C. The resulting solution was quenched by 50 mL of water andextracted with EtOAc (3×50 mL) and the organic layers combined. Thesolution was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified by silica gel column chromatographyeluting with EtOAc/petroleum ether (1:1) to afford 280 mg (18%) of titlecompound as a brown oil. LCMS [M+H]⁺ 611.

Step 4:6-[4-[(3R)-3-(2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)butanoyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(3S)-3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)butanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-[3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)butanoyl]piperazin-1-yl]pyridine-3-carbonitrile(250 mg, 0.52 mmol, 1.00 equiv), TFA (3 mL) in DCM (15 mL) was stirredfor 0.5 h at RT. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/ACN. The residue wasfurther purified by Prep-HPLC and Chiral-Prep-HPLC (CHIRAL PAK IG-3, 3μm, 0.46×5 cm column, eluting with Hexanes (0.1% DEA):DCM=3:1, at a flowrate of 1 mL/min) yielding (after arbitrary assignment ofstereochemistry) the title compounds as white solids.

Example 538 Isomer A

14.0 mg, 6%, LCMS [M+H]⁺ 481.30. ¹H NMR (300 MHz, Methanol-d₄) δ 8.42(s, 1H), 8.20 (s, 1H), 7.76 (dd, J=9.1, 2.4 Hz, 1H), 6.84 (d, J=9.1,1H), 4.53 (t, J=4.2 Hz, 2H), 4.09-3.87 (m, 2H), 3.83-3.56 (m, 9H), 2.77(dd, J=15.1, 8.1 Hz, 1H), 2.45 (dd, J=15.0, 4.4 Hz, 1H), 1.31-1.14 (m,3H). tR=2.027 min.

Example 538 Isomer B

24.5 mg, 5%, LCMS [M+H]⁺ 481.25, tR=2.848 min.

Example 539 Isomer A:(S)-5-(1-(3-(4-(5-Chloropyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yloxy)-4-(trifluoromethyl)pyridazin-3(2H)-oneand Example 539 Isomer B:(S)-5-(2-(3-(4-(5-Chloropyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)propoxy)-4-(trifluoromethyl)pyridazin-3(2H)-oneand Example 539 Isomer C:(R)-5-(2-(3-(4-(5-Chloropyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)propoxy)-4-(trifluoromethyl)pyridazin-3(2H)-oneand Example 539 Isomer D:(R)-5-(1-(3-(4-(5-Chloropyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yloxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

Step 1:1-[4-(5-Chloropyridin-2-yl)piperazin-1-yl]-3-(2-hydroxypropoxy)propan-1-oneand1-(4-(5-chloropyridin-2-yl)piperazin-1-yl)-3-(1-hydroxypropan-2-yloxy)propan-1-one

A solution of propane-1,2-diol (1.9 g, 25.3 mmol, 5.00 equiv), Cs₂CO₃(3.32 g, 10.2 mmol, 2.00 equiv), and Int-A22 (1.3 g, 5.1 mmol, 1.00equiv) in ACN (40 mL) was stirred for 6 h at 75° C. After concentration,the residue was purified by C18 reverse phase chromatography elutingwith H₂O/ACN to afford 800 mg (48%) of a mixture of title compounds as ayellow oil. LCMS [M+H]⁺ 328.14.

Step 2:5-[(1-[3-[4-(5-Chloropyridin-2-yl)piperazin-1-yl]-3-oxopropoxy]propan-2-yl)oxy]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-oneand5-(2-(3-(4-(5-chloropyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)propoxy)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one

A solution of1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-(2-hydroxypropoxy)propan-1-oneand1-(4-(5-chloropyridin-2-yl)piperazin-1-yl)-3-(1-hydroxypropan-2-yloxy)propan-1-onemixture (800 mg, 2.43 mmol, 1 equiv), Cs₂CO₃ (2.38 g, 7.32 mmol, 3equiv), and Int-A6 (2.38 g, 7.32 mmol, 3.00 equiv) in DMF (30 mL) wasstirred 6 h at 80° C. The solids were filtered and the resultingsolution was extracted with EtOAc (3×60 mL) and the organic layerscombined. The solution was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (1:1) to afford 1 g (66%) ofthe title compounds as yellow oil. LCMS [M+H]⁺ 620.23.

Step 3:(S)-5-(1-(3-(4-(5-Chloropyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yloxy)-4-(trifluoromethyl)pyridazin-3(2H)-oneand(S)-5-(2-(3-(4-(5-chloropyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)propoxy)-4-(trifluoromethyl)pyridazin-3(2H)-oneand(R)-5-(2-(3-(4-(5-chloropyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)propoxy)-4-(trifluoromethyl)pyridazin-3(2H)-oneand(R)-5-(1-(3-(4-(5-chloropyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yloxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of the mixture of5-[(1-[3-[4-(5-chloropyridin-2-yl)piperazin-1-yl]-3-oxopropoxy]propan-2-yl)oxy]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-oneand5-(2-[3-[4-(5-chloropyridin-2-yl)piperazin-1-yl]-3-oxopropoxy]propoxy)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-onemixture (750.0 mg, 1.21 mmol, 1.00 equiv) and TFA (4 mL) in DCM (20 mL)was stirred for 1 h at RT. After concentration, the residue was purifiedby C18 reverse phase chromatography eluting with H₂O/ACN and the residuewas further purified by Prep-HPLC and Chiral-Prep-HPLC (CHIRALPAK ID-3,3 μm, 0.46×10 cm column, eluting with MtBE (3% iPrNH₂):MeOH=80:20, at aflow rate of 1 mL/min) to afford Isomer A and D and by Prep-HPLC andChiral-Prep HPLC (CHIRALPAK IG-3, 3 μm, 0.46×10 cm column, eluting withMtBE (3% iPrNH₂):MeOH=80:20, at a flow rate of 1.0 mL/min) to affordIsomer B and C. The absolute stereochemistry of Example 539 Isomer A andD was assigned in analogy to Example 513A, based on the PARP7 potency ofthe more potent enantiomer and in analogy to the Example 513A X-ray. Theabsolute stereochemistry of the enantiomers of Isomers B and C wasarbitrarily assigned.

Example 539 Isomer A

57.4 mg, 29%, LCMS [M+H]⁺ 490.20. ¹H NMR (300 MHz, Methanol-d₄) δ 8.21(s, 1H), 8.06 (s, 1H), 7.53 (dd, J=9.1, 2.7 Hz, 1H), 6.79 (d, J=9.1 Hz,1H), 5.13-5.06 (m, 1H), 3.85-3.78 (m, 1H), 3.75-3.54 (m, 7H), 3.51-3.48(m, 4H), 2.62 (t, J=6.0 Hz, 2H), 1.34 (d, J=6.3 Hz, 3H). tR=2.064 min

Example 539 Isomer B

LCMS [M+H]⁺ 490.20, ¹H NMR (300 MHz, Methanol-d₄) δ 8.18 (s, 1H), 8.05(s, 1H), 7.53 (dd, J=9.1, 2.7 Hz, 1H), 6.79 (d, J=9.1 Hz, 1H), 4.40-4.31(m, 2H), 3.93-3.79 (m, 3H), 3.78-3.65 (m, 4H), 3.56-3.45 (m, 4H), 2.65(t, J=6.0 Hz, 2H), 1.24 (d, J=6.4 Hz, 3H). tR=2. 485 min.

Example 539 Isomer C

28.2 mg, 14%, LCMS [M+H]⁺ 490.20, tR=3.126 min.

Example 539 Isomer D

26.7 mg, 14%, LCMS [M+H]⁺ 490.20, tR=3.919 min.

Example 540:6-(4-[3-[(1-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]-2,3-dihydro-1H-inden-2-yl)oxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1:6-(4-[3-[(1-Hydroxy-2,3-dihydro-1H-inden-2-yl)oxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of 2,3-dihydro-1H-indene-1,2-diol (900 mg, 5.99 mmol, 3.00equiv), Int-A25 (500 mg, 2.06 mmol, 1.00 equiv) and Cs₂CO₃ (4000 mg,12.28 mmol, 6.00 equiv) in ACN (20 mL) was stirred for 2 h at 35° C.,and then the solids were filtered and the resulting solution wasconcentrated under vacuum, and then the residue was purified by C18reverse phase chromatography eluting with H₂O/ACN to afford 620 mg (77%)of title compound as a white solid. LCMS [M+H]⁺ 393.19.

Step 2:6-(4-[3-[(1-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]-2,3-dihydro-1H-inden-2-yl)oxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-(4-[3-[(1-hydroxy-2,3-dihydro-1H-inden-2-yl)oxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile(150 mg, 0.38 mmol, 1 equiv), Cs₂CO₃ (249.1 mg, 0.76 mmol, 2 equiv) andInt-A6 (188.5 mg, 0.57 mmol, 1.5 equiv) in ACN (2 mL) was stirred for 1h at 60° C., and then the solids were filtered out and the resultingsolution was concentrated under vacuum. The residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN to afford 180 mg(69%) of title compound as a yellow oil. LCMS [M+H]⁺ 685.27.

Step 3:6-(4-[3-[(1-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]-2,3-dihydro-1H-inden-2-yl)oxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-(4-[3-[(1-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]-2,3-dihydro-1H-inden-2-yl)oxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile(80 mg, 0.16 mmol, 1 equiv) and TFA (0.5 mL) in DCM (2 mL) was stirredfor 30 min at RT, and then the resulting solution was concentrated undervacuum, and then the residue was purified by C18 reverse phasechromatography eluting with H₂O/ACN. Then the residue was furtherpurified by Prep-HPLC to afford the title compound (3.7 mg, 6%) as awhite solid. LCMS [M+H]⁺ 555.15. ¹H NMR (300 MHz, Methanol-d4) δ 8.43(d, J=1.8 Hz, 1H), 8.39 (s, 1H), 7.78 (dd, J=9.0, 2.4 Hz, 1H), 7.46 (d,J=6.9 Hz, 1H), 7.32-7.26 (m, 3H), 6.83 (dd, J=9.1, 0.9 Hz, 1H), 5.63 (q,J=5.3 Hz, 1H), 5.16 (d, J=4.8 Hz, 1H), 4.08-3.88 (m, 2H), 3.78-3.59 (m,8H), 3.36 (d, J=16.4 Hz, 1H), 3.28 (dd, J=16.3, 4.9 Hz, 1H), 2.73-2.50(m, 2H).

Example 541:6-(4-[3-[(1S,2R)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]cyclobutoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1:5-[[(2S)-2-Hydroxycyclobutyl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of Int-A6 (1.3 g, 3.95 mmol, 1 equiv),(1R,2S)-2-aminocyclobutan-1-ol hydrochloride (0.5 g, 4.05 mmol, 1.02equiv), TEA (0.8 g, 7.91 mmol, 2.00 equiv) in EtOH (20 mL) was stirredfor 1 hr at 60° C. The resulting mixture was concentrated under vacuum.The residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1/4) to afford 900 mg (60%) of title compound asa yellow oil. LCMS [M+H]⁺ 380.15.

Step 2: Methyl3-[(1S,2R)-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]cyclobutoxy]propanoate

A solution of5-[[(2S)-2-hydroxycyclobutyl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(900 mg, 2.37 mmol, 1 equiv), Cs₂CO₃ (1500 mg, 4.60 mmol, 1.94 equiv),methyl prop-2-enoate (412 mg, 4.79 mmol, 2.02 equiv) in ACN (20 mL) wasstirred for 6 hr at RT. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1/4) to afford 750 mg (68%) of title compound asa yellow oil. LCMS [M+H]⁺ 466.19.

Step 3: Methyl3-[(1S,2R)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]cyclobutoxy]propanoate

A solution of methyl3-[(1S,2R)-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]cyclobutoxy]propanoate(750 mg, 1.61 mmol, 1 equiv), TFA (1 mL) in DCM (10 mL) was stirred for16 h at RT. The resulting mixture was concentrated under vacuum toafford 770 mg crude of title compound as a yellow oil. LCMS [M+H]⁺336.11.

Step 4: Synthesis of3-[(1S,2R)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]cyclobutoxy]propanoicAcid

A solution of methyl3-[(1S,2R)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]cyclobutoxy]propanoate(770 mg, 2.30 mmol, 1 equiv), LiOH.H₂O (290 mg, 6.91 mmol, 3.01 equiv)in MeOH (10 mL) was stirred for 3 h at RT. The pH value of the solutionwas adjusted to 4 with HCl (1 mol/L). The resulting mixture wasconcentrated under vacuum. After concentration, the residue was purifiedby C18 reverse phase chromatography eluting with H₂O/CH₃CN to afford 340mg (46%) of title compound as a white solid. LCMS [M+H]⁺ 322.09.

Step 5:6-(4-[3-[(1S,2R)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]cyclobutoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of3-[(1S,2R)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]cyclobutoxy]propanoicacid (300 mg, 0.93 mmol, 1 equiv), HATU (389.5 mg, 1.02 mmol, 1.10equiv), Int-A4 (193.7 mg, 1.03 mmol, 1.10 equiv), DIPEA (242.3 mg, 1.87mmol, 2.01 equiv) in DMF (5 mL) was stirred for 1 h at RT. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN and then the residue was furtherpurified by Prep-HPLC to afford the title compound (154.5 mg, 34%) as awhite solid. LCMS [M+H]⁺ 492.2. ¹H NMR (300 MHz, DMSO-d6) δ 12.60 (s,1H), 8.52 (d, J=2.3 Hz, 1H), 7.89 (dd, J=9.1, 2.4 Hz, 1H), 7.66 (s, 1H),6.95 (d, J=9.1 Hz, 1H), 6.66-6.57 (m, 1H), 4.37-4.34 (m, 1H), 4.33-4.20(m, 1H), 3.77-3.55 (m, 10H), 2.64 (t, J=6.3 Hz, 2H), 2.21-2.06 (m, 2H),2.10-1.93 (m, 1H), 1.80 (m, 1H).

Example 542:6-(4-[3-[3-(Dimethylamino)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1: Tert-butyl 3-[3-(dimethylamino)-2-hydroxypropoxy]propanoate

A solution of 3-(dimethylamino)propane-1,2-diol (2.38 g, 19.97 mmol, 1equiv), tert-butyl prop-2-enoate (2.6 g, 0.02 mmol, 1 equiv), and Cs₂CO₃(9.8 g, 30.08 mmol, 1.51 equiv) in ACN (30 mL) was stirred for 3 h atRT. The solids were filtered and the resulting mixture was concentratedto afford 400 mg (8%) of title compound as an oil. LCMS [M+H]⁺ 248.18.

Step 2:3-[3-(Dimethylamino)-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoate

A solution of tert-butyl3-[3-(dimethylamino)-2-hydroxypropoxy]propanoate (400 mg, 1.62 mmol, 1equiv), Int-A6 (531.7 mg, 1.62 mmol, 1.00 equiv), Cs₂CO₃ (790.4 mg, 2.43mmol, 1.5 equiv) in DMF (5 mL) was stirred for 3 h at 100° C. Thereaction was then quenched by the addition of 20 mL of water. Theresulting solution was extracted with 3×10 mL of EtOA and the residuewas purified by silica gel column chromatography with EtOAc/petroleumether (2/3) to afford 116 mg (13%) of title compound as a yellow oil.LCMS [M+H]⁺ 540.30.

Step 3:3-[3-(Dimethylamino)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoicAcid

A solution of tert-butyl3-[3-(dimethylamino)-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoate(116 mg, 0.21 mmol, 1 equiv), 2,2,2-trifluoroacetaldehyde (1 mL) in DCM(4 mL) was stirred for 4 h at RT. The resulting mixture was concentratedto afford 72 mg (95%) of title compound as a solid. LCMS [M+H]⁺ 354.05.

Step 4:6-(4-[3-[3-(Dimethylamino)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of3-[3-(dimethylamino)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoicacid (72 mg, 0.20 mmol, 1 equiv), Int-A4 (38.4 mg, 0.20 mmol, 1.00equiv), HATU (77.5 mg, 0.20 mmol, 1 equiv), DIPEA (79.0 mg, 0.61 mmol, 3equiv) in DMF (3 mL) was stirred for 2 h at RT. The reaction was thenquenched by the addition of 10 mL of water. The resulting solution wasextracted with 3×5 mL of EtOA. The organic layers were combined andconcentrated. The residue was applied onto a silica gel column withDCM/MeOH (6/1) and the crude product was further purified by Prep-HPLCto afford the title compound (7.1 mg, 7%) as a white solid. LCMS [M+H]⁺524.10. ¹H NMR (400 MHz, Methanol-d₄) δ 8.43 (s, 1H), 8.25 (s, 1H), 7.78(dd, J=9.1, 2.4 Hz, 1H), 6.87 (d, J=9.2 Hz, 1H), 5.16 (d, J=7.4 Hz, 1H),3.88-3.79 (m, 1H), 3.83-3.58 (m, 12H), 2.79-2.60 (m, 3H), 2.57 (dd,J=13.8, 3.5 Hz, 1H), 2.41 (s, 1H), 2.30 (s, 6H).

Example 543 Isomer A

(S)-5-(1-(3-(4-(5-Chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yloxy)-4-(trifluoromethyl)pyridazin-3(2H)-one and

Example 543 Isomer B

(S)-5-(2-(3-(4-(5-Chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propoxy)-4-(trifluoromethyl)pyridazin-3(2H)-one and

Example 543 Isomer C

(R)-5-(2-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propoxy)-4-(trifluoromethyl)pyridazin-3(2H)-one and

Example 543 Isomer D

(R)-5-(1-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yloxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

Step 2:1-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-3-(2-hydroxypropoxy)propan-1-oneand1-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-(1-hydroxypropan-2-yloxy)propan-1-one

A solution of Int-A23 (1.5 g, 5.94 mmol, 1 equiv), Cs₂CO₃ (3.9 g, 11.87mmol, 2 equiv), and propane-1,2-diol (2.3 g, 30.21 mmol, 5.09 equiv) inACN (40 mL) was stirred for 4 h at 75° C. After concentration, theresidue was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN to afford 1.4 g (72%) of the mixture of the title compounds aswhite solids. LCMS [M+H]⁺ 329.12.

Step 3:5-[(1-[3-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]propan-2-yl)oxy]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-oneand5-(2-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propoxy)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one

A solution of the mixture of1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-(2-hydroxypropoxy)propan-1-oneand1-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-(1-hydroxypropan-2-yloxy)propan-1-one(1.4 g, 4.26 mmol, 1 equiv), Cs₂CO₃ (4.2 g, 12.77 mmol, 3 equiv), andInt-A6 (4.2 g, 12.77 mmol, 3.00 equiv) in DMF (30 mL) was stirred for 4h at 80° C. The solids were filtered out and the resulting solution wasquenched by 50 mL of water and extracted with EtOAc (3×30 mL). Theorganic layers were combined and the solution was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column eluting with EtOAc/petroleum ether (1:1) toafford 1.07 g (40%) of the mixture of the title compounds as a yellowoil. LCMS [M+H]⁺ 621.22.

Step 4: Mixture of(S)-5-(1-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yloxy)-4-(trifluoromethyl)pyridazin-3(2H)-one,(S)-5-(2-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propoxy)-4-(trifluoromethyl)pyridazin-3(2H)-one,(R)-5-(2-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propoxy)-4-(trifluoromethyl)pyridazin-3(2H)-oneand(R)-5-(1-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yloxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of the mixture of5-(2-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]propoxy)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-oneand5-[(1-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]propan-2-yl)oxy]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1 g, 1.60 mmol, 1.00 equiv), TFA (4 mL) in DCM (20 mL) was stirred for1 h at RT. After concentration, the residue was purified by C18 reversephase chromatography eluting with H₂O/ACN. The residue was furtherpurified by Prep-HPLC and Chiral-Prep-HPLC (CHIRALPAK ID-3, 3 μm,0.46×10 cm column, eluting with MtBE (0.01M NH₃):MeOH=80:20, at a flowrate of 1 mL/min) to afford the title compounds as white solids. Thestereochemistry of isomer A and isomer D was assigned in analogy toExample 513A, based on the PARP7 potency of the more potent enantiomerand in analogy to the Example 513A X-ray.

The absolute stereochemistry for isomer B and C was arbitrarilyassigned. (The position of the methyl group was confirmed by ¹H-NMR).

Example 543 Isomer A

102.8 mg, 26%, LCMS [M+H]⁺ 491.1 ¹H NMR (300 MHz, Methanol-d4) δ 8.31(s, 2H), 8.21 (s, 1H), 5.11 (t, J=6.7 Hz, 1H), 3.88-3.53 (m, 12H), 2.63(t, J=5.8 Hz, 2H), 1.34 (d, J=6.3 Hz, 3H), tR=2.283 min.

Example 543 Isomer B

95.9 mg, 24%, LCMS [M+H]⁺ 491.1. ¹H NMR (300 MHz, Methanol-d4) δ 8.30(s, 2H), 8.19 (s, 1H), 4.43-4.29 (m, 2H), 3.93-3.86 (m, 2H), 3.86-3.74(m, 5H), 3.93-3.86 (m, 4H), 2.65 (t, J=6.0 Hz, 2H), 1.24 (d, J=6.4 Hz,3H). tR=2.890 min.

Example 543 Isomer C

87.6 mg, 21%, LCMS [M+H]⁺ 491.1, tR=3.584 min.

Example 543 Isomer D

91.8 mg, 23%, LCMS [M+H]⁺ 491.1, tR=6.313 min.

Example 544 Isomer A:(S)-5-(1-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yloxy)-4-(trifluoromethyl)pyridazin-3(2H)-oneand Example 544 Isomer B:(R)-5-(1-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yloxy)-4-(trifluoromethyl)pyridazin-3(2H)-oneand Example 544 Isomer C:(S)-5-(2-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propoxy)-4-(trifluoromethyl)pyridazin-3(2H)-oneand Example 544 Isomer D:(R)-5-(2-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propoxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

Step 1: Mixture of3-(2-hydroxypropoxy)-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propan-1-oneand3-(1-hydroxypropan-2-yloxy)-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propan-1-one

A solution of Int-A21 (1 g, 3.49 mmol, 1.00 equiv), propane-1,2-diol(1.33 g, 17.48 mmol, 5.00 equiv), and Cs₂CO₃ (2.3 g, 7.06 mmol, 2.00equiv) in ACN (30 mL) was stirred for 8 h at 75° C. After concentration,the residue was purified by C18 reverse phase chromatography elutingwith H₂O/ACN to afford 930 mg (73%) of the mixture of the titlecompounds mixture as a white solid. LCMS [M+H]⁺ 363.17.

Step 2: Mixture of5-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yloxy)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-oneand5-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propoxy)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one

A solution of the mixture of3-(2-hydroxypropoxy)-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propan-1-oneand3-(1-hydroxypropan-2-yloxy)-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propan-1-onemixture (1.3 g, 3.59 mmol, 1.00 equiv), Int-A6 (1.4 g, 4.26 mmol, 1.20equiv), and Cs₂CO₃ (3.5 g, 10.74 mmol, 3.00 equiv) in DMF (15 mL) wasstirred for 6 h at 80° C. The solids were filtered and the resultingsolution was quenched by water (50 mL) and extracted with EtOAc (3×60mL) and the organic layers combined. The solution was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column eluting with EtOAc/hexane (1:1) toafford 1.6 g (68%) of the title compounds as yellow oil. LCMS [M+H]⁺655.25.

Step 3:(S)-5-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yloxy)-4-(trifluoromethyl)pyridazin-3(2H)-one,(R)-5-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yloxy)-4-(trifluoromethyl)pyridazin-3(2H)-one,(S)-5-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1yl)propoxy)propoxy)-4-(trifluoromethyl)pyridazin-3(2H)-one and(R)-5-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propoxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of5-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yloxy)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-oneand5-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propoxy)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one mixture (1.54 g, 2.35 mmol, 1 equiv), and TFA (2 mL) in DCM (10mL) was stirred for 0.5 h at RT. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/ACN. Theresidue was further purified by Prep-HPLC and Chiral-Prep-HPLC (LuxAmylose-1, 3 μm, 4.6×100 mm column, eluting with EtOH (0.1% DEA), at aflow rate of 4 mL/min). The absolute stereochemistry of isomer A and Bwas assigned in analogy to Example 513A, based on the PARP7 potency ofthe more potent enantiomer and in analogy to the Example 513A X-ray. Theabsolute stereochemistry for isomer C and isomer D was arbitrarilyassigned. (The position of methyl group was confirmed by ¹H-NMR).Isomers A-D were isolated as white solids.

Example 544 Isomer A

102.5 mg, 8%, LCMS [M+H]⁺ 525.25. ¹H NMR (300 MHz, Methanol-d₄) δ 8.61(s, 2H), 8.23 (s, 1H), 5.16-5.09 (m, 1H), 3.99-3.78 (m, 4H), 3.81-3.68(m, 1H), 3.67 (m, 1H), 3.65-3.56 (m, 6H), 2.71-2.61 (t, J=5.7 Hz, 2H),1.37 (d, J=6.3 Hz, 3H). tR=1.369 min.,

Example 544 Isomer B

56.3 mg, 5%, LCMS [M+H]⁺ 525.20, tR=1.636 min.

Example 544 Isomer C

39 mg, 3%, LCMS [M+H]⁺ 525.25, ¹H NMR (300 MHz, Methanol-d₄) δ 8.60 (s,2H), 8.22 (s, 1H), 4.47-4.32 (m, 2H), 4.00-3.75 (m, 7H), 3.70-3.68 (m,4H), 2.68 (t, J=6.0 Hz, 2H), 1.27 (d, J=6.4 Hz, 3H). tR=2.835 min.

Example 544 Isomer D

27.2 mg, 2%, LCMS [M+H]⁺ 525.25, tR=2.039 min.

Example 545 Isomer A:5-[[(2S,5S)-5-(2-Oxo-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand Example 545 Isomer B:5-[[(2S,5R)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand Example 545 Isomer C:5-[[(2R,5R)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand Example 545 Isomer D:5-[[(2R,5S)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1:5-[[5-(2-Oxo-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of Int-A17 (700 mg, 1.87 mmol, 1 equiv), Int-A6 (1849.2 mg,5.62 mmol, 3.00 equiv), and Cs₂CO₃ (1.8 g, 5.62 mmol, 3 equiv) in ACN(10 mL) was stirred for 2 h at 80° C. The solids were filtered and theresulting mixture was concentrated under reduced pressure. The residuewas purified by silica gel column chromatography eluting withEtOAc/petroleum ether (99/1) to afford 788 mg (63%) of title compound asa yellow oil. LCMS [M+H]⁺ 666.10.

Step 2:5-[[(2S,5S)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one,5-[[(2S,5R)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one,5-[[(2R,5R)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand5-[[(2R,5S)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution5-[[5-(2-oxo-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(888 mg, 1.33 mmol, 1 equiv) and TFA (2 mL) in DCM (10 mL) was stirredfor 3 h at RT. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/ACN. The residue was thenfurther purified by Prep-HPLC and Chiral-Prep-HPLC (CHIRALPAK IA-3, 3μm, 0.46×5 cm column, eluting with hexane:DCM (5:1)/(0.1%TEA):EtOH=85:15, at a flow rate of 1 mL/min) yielding (after arbitraryassignment of stereochemistry) the title compounds.

Example 545 Isomer A

18.4 mg, 3%, LCMS [M+H]⁺ 536.30. ¹H NMR (300 MHz, Methanol-d₄) δ 8.37(d, J=2.3 Hz, 1H), 8.25 (d, J=0.9 Hz, 1H), 7.75 (dd, J=9.1, 2.5 Hz, 1H),6.88 (d, J=9.1 Hz, 1H), 4.56 (dd, J=10.7, 3.2 Hz, 1H), 4.47-4.23 (m,3H), 3.72 (tdd, J=17.5, 13.2, 8.4 Hz, 8H), 2.78 (dd, J=15.0, 7.7 Hz,1H), 2.58 (dd, J=14.9, 4.9 Hz, 1H), 2.27-1.90 (m, 2H), 1.98-1.88 (m,1H), 1.83-1.66 (m, 1H). tR=2.571 min.

Example 545 Isomer B

17.2 mg, 2%, LCMS [M+H]⁺ 536.30. ¹H NMR (300 MHz, Methanol-d₄) δ 8.38(dt, J=2.7, 0.9 Hz, 1H), 8.23 (d, J=0.8 Hz, 1H), 7.76 (dd, J=9.0, 2.5Hz, 1H), 6.90 (d, J=9.1 Hz, 1H), 4.54-4.31 (m, 4H), 3.86-3.66 (m, 8H),3.71-3.57 (m, 2H), 2.83 (dd, J=14.5, 7.8 Hz, 1H), 2.59 (dd, J=14.5, 4.8Hz, 1H), 2.33-2.12 (m, 2H), 2.01-1.65 (m, 2H), tR=3.197 min.

Example 545 Isomer C

16.7 mg 2%, LCMS [M+H]⁺ 536.30, ¹H NMR (300 MHz, Methanol-d₄) δ 8.37(dt, J=2.8, 0.9 Hz, 1H), 8.25 (d, J=0.8 Hz, 1H), 7.80-7.70 (m, 1H), 6.88(d, J=9.1 Hz, 1H), 4.56 (dd, J=10.7, 3.2 Hz, 1H), 4.47-4.23 (m, 3H),3.72 (tdd, J=17.5, 13.2, 8.4 Hz, 8H), 2.78 (dd, J=14.9, 7.7 Hz, 1H),2.58 (dd, J=14.9, 4.9 Hz, 1H), 2.27-2.08 (m, 2H), 2.02-1.89 (m, 1H).1.83-1.64 (m, 1H), tR=5.305 min.

Example 545 Isomer D

18.4 mg, 3%, LCMS [M+H]⁺ 536.30, ¹H NMR (300 MHz, Methanol-d₄) δ 8.38(dt, J=2.7, 1.0 Hz, 1H), 8.22 (d, J=0.8 Hz, 1H), 7.76 (dd, J=9.1, 2.6Hz, 1H), 6.90 (d, J=9.1 Hz, 1H), 4.54-4.31 (m, 4H), 3.86-3.63 (m, 8H),2.83 (dd, J=14.6, 7.7 Hz, 1H), 2.59 (dd, J=14.5, 4.8 Hz, 1H), 2.33-2.17(m, 2H), 2.01-1.65 (m, 2H), tR=6.548 min.

Example 546 Isomer A:5-([[(2S,5S)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methyl]amino)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand Example 546 Isomer B:5-([[(2R,5R)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methyl]amino)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand Example 546 Isomer C:5-([[(2S,5R)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methyl]amino)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand Example 546 Isomer D:5-([[(2R,5S)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methyl]amino)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1:2-[5-(Azidomethyl)oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethan-1-one

A solution of Int-A17 (1 g, 2.68 mmol, 1 equiv), DPPA (3.7 g, 13.44mmol, 5.02 equiv), and DBU (1.2 g, 8.03 mmol, 3 equiv) was stirred for 2days at 80° C. The resulting mixture was concentrated under reducedpressure and the residue purified by silica gel column chromatographywith EtOAc/petroleum ether (2/3) to afford 500 mg (47%) of titlecompound as a yellow oil. LCMS [M+H]⁺ 399.17.

Step 2:2-[5-(Aminomethyl)oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethan-1-one

A solution of2-[5-(azidomethyl)oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethan-1-one(550 mg, 1.38 mmol, 1 equiv), Pd/C (100 mg, 0.94 mmol, 0.68 equiv) inMeOH was stirred for 2 h at RT under H₂ (g) atmosphere. The solids werefiltered and the resulting mixture was concentrated under reducedpressure to afford 360 mg (70%) of title compound as a yellow oil. LCMS[M+H]⁺ 373.19.

Step 3:5-([[5-(2-Oxo-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methyl]amino)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of Int-A6 (317.8 mg, 0.97 mmol, 1.00 equiv),2-[5-(aminomethyl)oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethan-1-one(360 mg, 0.97 mmol, 1 equiv), TEA (195.6 mg, 1.93 mmol, 2 equiv) in EtOH(10 mL) was stirred for 2 h at 50° C. The resulting mixture wasconcentrated under reduced pressure and the residue was applied onto asilica gel column with DCM/MeOH (9/1) to afford 520 mg (81%) of titlecompound as a yellow oil. LCMS [M+H]⁺ 665.26.

Step 4:5-([[(2S,5S)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methyl]amino)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one,5-([[(2R,5R)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methyl]amino)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one,5-([[(2S,5R)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methyl]amino)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand5-([[(2R,5S)-5-(2-oxo-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methyl]amino)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-([[5-(2-oxo-2-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methyl]amino)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(520 mg, 0.78 mmol, 1 equiv), and 2,2,2-trifluoroacetaldehyde (2 mL,0.02 mmol, 0.03 equiv) in DCM (8 mL) was stirred for 5 h at RT. Afterconcentration under reduced pressure, the residue was purified by C18reverse phase chromatography eluting with H₂O/ACN. Then the residue wasfurther purified by Prep-HPLC and Chiral-Prep-HPLC (CHIRALPAK IE-3, 3μm, 0.46×10 cm column, eluting with (Hex:DCM=5:1)(0.1% DEA):EtOH=50:50,at a flow rate of 1 mL/min) yielding (after arbitrary assignment ofstereochemistry) the title compounds.

Example 546 Isomer A

16.4 mg, 4%, LCMS [M+H]⁺ 535.10, ¹H NMR (300 MHz, DMSO-d6) δ 12.41 (s,1H), 8.44 (s, 1H), 7.94 (s, 1H), 7.83 (dd, J=9.0, 2.6 Hz, 1H), 6.95 (d,J=8.9 Hz, 2H), 4.17 (q, J=6.3 Hz, 1H), 4.08-3.90 (m, 1H), 3.76-3.35 (m,10H), 2.62 (dd, J=15.3, 6.4 Hz, 1H), 2.45-2.35 (m, 1H), 2.05-1.89 (m,2H), 1.70 (dq, J=12.1, 6.4 Hz, 1H), 1.62-1.47 (m, 1H). tR=2.294 min.

Example 546 Isomer B

27.2 mg, 7%, LCMS [M+H]⁺ 535.10, ¹H NMR (300 MHz, DMSO-d6) δ 12.38 (s,1H), 8.42 (d, J=2.5 Hz, 1H), 7.91 (s, 1H), 7.82 (dd, J=9.1, 2.6 Hz, 1H),6.94 (d, J=9.0 Hz, 2H), 4.27 (q, J=6.4 Hz, 1H), 4.18-4.10 (m, 1H),3.85-3.45 (m, 10H), 2.69 (dd, J=15.1, 6.5 Hz, 1H), 2.50-2.39 (m, 1H),2.09 (dd, J=11.2, 6.6 Hz, 1H), 2.18-1.90 (m, 2H), 1.78-1.60 (m, 2H).tR=2.793 min.

Example 546 Isomer C

40.6 mg, 10%, LCMS [M+H]⁺ 535.10, ¹H NMR (300 MHz, DMSO-d6) δ 12.39 (s,1H), 8.42 (d, J=2.4 Hz, 1H), 7.91 (s, 1H), 7.82 (dd, J=9.2, 2.6 Hz, 1H),6.94 (d, J=9.0 Hz, 2H), 4.25 (q, J=6.3 Hz, 1H), 4.18-4.10 (m, 1H),3.80-3.40 (m, 10H), 2.69 (dd, J=15.2, 6.5 Hz, 1H), 2.49-2.39 (m, 1H),2.08-1.90 (m, 2H), 1.80-1.60 (m, 2H). tR=3.208 min.

Example 546 Isomer D

11.1 mg, 3%, LCMS [M+H]⁺ 535.10, ¹H NMR (300 MHz, DMSO-d6) δ 12.41 (s,1H), 8.43 (s, 1H), 7.94 (s, 1H), 7.83 (dd, J=9.1, 2.6 Hz, 1H), 6.95 (d,J=9.0 Hz, 2H), 4.18 (t, J=6.6 Hz, 1H), 4.08-3.90 (m, 1H), 3.69-3.36 (m,10H), 2.62 (dd, J=15.4, 6.4 Hz, 1H), 2.41 (dd, J=15.4, 6.3 Hz, 1H),2.11-1.85 (m, 2H), 1.69 (s, 1H), 1.59-1.47 (m, 1H). tR=4.088 min

Example 547:4-Bromo-5-(2-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]ethoxy)-2,3-dihydropyridazin-3-one

Step 1:4-Bromo-5-(2-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]ethoxy)-2,3-dihydropyridazin-3-one

A solution of Int-A14 (150 mg, 0.49 mmol, 1 equiv), HOBT (99.0 mg, 0.73mmol, 1.5 equiv), EDCI (140.5 mg, 0.73 mmol, 1.5 equiv), DIPEA (189.4mg, 1.47 mmol, 3 equiv) and Int-A3 (97.0 mg, 0.49 mmol, 1.00 equiv) inDMF (7 mL, 0.10 mmol, 0.20 equiv) was stirred for 1 h at RT, and thenthe resulting solution was purified by C18 reverse phase chromatographyeluting with H₂O/CH₃CN and further purified by Prep-HPLC to afford thetitle compound as a white solid (13.3 mg, 6%). LCMS [M+H]⁺ 489.10 [M+H],¹H NMR (300 MHz, DMSO-d₆) δ 13.16 (s, 1H), 8.43 (s, 2H), 8.07 (s, 1H),4.47-4.50 (m, 2H), 3.75-3.66 (m, 8H), 3.60-3.52 (m, 4H), 2.64 (t, J=6.5Hz, 2H).

The following example in Table E6 was similarly prepared from Int-A14and the appropriate intermediate Int-A2 according to the methoddescribed for Example 547.

TABLE E6 Example Name, structure, analytical data Int. Example 548

Int-A2 and Int-A144-Bromo-5-[2-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)ethoxy]-2,3-dihydropyridazin-3-one; LCMS: [M +H]⁺ 522.95; ¹H NMR (300 MHz, DMSO-d₆) δ 8.72 (s, 2H), 8.08 (s, 1H),4.48-4.45 (m, 2H), 3.84-3.72 (m, 8H), 3.62-3.55 (m, 4H), 2.65 (t, J =6.5 Hz, 2H).

Example 549:5-(2-[3-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]ethoxy)-4-methyl-2,3-dihydropyridazin-3-one

Step 1:5-(2-[3-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]ethoxy)-4-methyl-2,3-dihydropyridazin-3-one

A solution of Int-A15 (300 mg, 1.24 mmol, 1 equiv), Int-A3 (370.0 mg,1.36 mmol, 1.1 equiv), DIPEA (480.2 mg, 3.72 mmol, 3 equiv), and HATU(518.0 mg, 1.36 mmol, 1.1 equiv) in DMF (8 mL) was stirred 2 h at 25° C.After concentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/ACN and the residue was further purifiedby Prep-HPLC to afford the title compound (76.3 mg, 15%) as a whitesolid. LCMS [M+H]⁺ 423.15, ¹H NMR (300 MHz, DMSO-d₆) δ 12.78 (s, 1H),8.44 (s, 2H), 8.01 (s, 1H), 4.36-4.27 (m, 2H), 3.80-3.63 (m, 8H), 3.54(d, J=5.8 Hz, 4H), 2.63 (t, J=6.5 Hz, 2H), 1.85 (s, 3H).

The following examples in Table E7 were similarly prepared from Int-A15and the appropriate intermediates according to the method described forExample 549.

TABLE E7 Example Name, structure, analytical data Int. Example 550

Int-A2 and Int-A154-Methyl-5-[2-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)ethoxy]-2,3-dihydropyridazin-3-one; LCMS: [M +H]⁺ 457.17; ¹H NMR (300 MHz, DMSO-d₆) δ: 12.76 (s, 1H), 8.70 (d, J = 0.9Hz, 2H), 7.99 (s, 1H), 4.30 (dd, J = 5.5, 3.4 Hz, 2H), 3.79 (dd, J =15.3, 5.5 Hz, 4H), 3.74-3.65 (m, 4H), 3.55 (s, 4H), 2.61 (t, J = 6.5 Hz,2H), 1.83 (s, 3H). Example 551

Int-A4 and Int- A156-[4-(3-[2-[(5-Methyl-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile; LCMS: [M + H]⁺413.19; ¹H NMR (300 MHz, DMSO-d6) δ 8.51 (d, J = 2.3 Hz, 1H), 8.02 (s,1H), 7.88 (dd, J = 9.1, 2.4 Hz, 1H), 6.92 (d, J = 9.1 Hz, 1H), 4.37-4.28(m, 2H), 3.78-3.53 (m, 12H), 2.64 (t, J = 6.5 Hz, 2H), 1.86 (s, 3H).

Example 552:5-(2-[3-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]ethoxy)-3-oxo-2,3-dihydropyridazine-4-carbonitrile

Step 1:5-(2-[3-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]ethoxy)-3-oxo-2,3-dihydropyridazine-4-carbonitrile

A solution of Int-A16 (150 mg, 0.59 mmol, 1 equiv), EDCI (124.8 mg, 0.65mmol, 1.10 equiv), HOBT (88 mg, 0.65 mmol, 1.10 equiv), and Int-A3 (130mg, 0.65 mmol, 1.10 equiv) in DMF (15 mL) was stirred for 1.5 h at RT.After concentration under reduced pressure, the residue was purified byC18 reverse phase chromatography eluting with H₂O/ACN and the residuewas further purified by Prep-HPLC to afford (34.8 mg, 14%) as a whitesolid. LCMS [M+H]⁺ 433.85, ¹H NMR (300 MHz, DMSO-d6) δ 13.52 (s, 1H),8.45 (s, 2H), 8.30 (s, 1H), 4.65-4.57 (m, 2H), 3.81-3.64 (m, 8H), 3.34(s, 4H), 2.63 (t, J=6.4 Hz, 2H).

The following example in Table E8 was similarly prepared from Int-A16and the appropriate intermediate, Int-A2, according to the methoddescribed for Example 552.

TABLE E8 Example Name, structure, analytical data Int. Example 553

Int-A2 and Int-A163-Oxo-5-[2-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)ethoxy]-2,3-dihydropyridazine-4-carbonitrile; LCMS: [M +H]⁺ 468.2; ¹H NMR (300 MHz, DMSO-d6) δ 13.49 (s, 1H), 8.70 (d, J = 0.9Hz, 2H), 8.27 (s, 1H), 4.58 (dd, J = 5.1, 3.2 Hz, 2H), 3.98-3.76 (m,8H), 3.55 (t, J = 5.3 Hz, 4H), 2.61 (t, J = 6.4 Hz, 2H).

Example 554:5-(2-[3-[4-(5-Cyanopyridin-2-yl)piperazin-1-yl]-3-oxopropoxy]ethoxy)-3-oxo-2,3-dihydropyridazine-4-carbonitrile

Step 1:5-(2-[3-[4-(5-Cyanopyridin-2-yl)piperazin-1-yl]-3-oxopropoxy]ethoxy)-3-oxo-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazine-4-carbonitrile

A solution of Int-A19 (130 mg, 0.21 mmol, 1 equiv) and CuCN (40 mg, 0.45mmol, 2.09 equiv) in NMP (10 mL) was stirred 1 day at 120° C. Thereaction was then quenched by the addition of 20 mL of water. Theresulting solution was extracted with EtOAc and the organic layers werecombined and dried over anhydrous sodium sulfate. After concentration,the residue was purified by C18 reverse phase chromatography elutingwith H₂O/ACN to afford 50 mg (42%) of title compound as a yellow oil.LCMS [M+H]⁺ 554.25.

Step 2:5-(2-[3-[4-(5-Cyanopyridin-2-yl)piperazin-1-yl]-3-oxopropoxy]ethoxy)-3-oxo-2,3-dihydropyridazine-4-carbonitrile

A solution of5-(2-[3-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-3-oxopropoxy]ethoxy)-3-oxo-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazine-4-carbonitrile(50 mg, 0.09 mmol, 1 equiv) in HCl/dioxane (2 mL) was stirred for 24 hat RT. The solvent was concentrated under vacuum and the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CNfollowed by further purification by Prep-HPLC to afford the titlecompound (3.4 mg, 9%) as a white solid. LCMS [M+H]⁺ 424.3, ¹H NMR (300MHz, DMSO-d6) δ 8.50 (d, J=2.4 Hz, 1H), 8.29 (s, 1H), 7.87 (dd, J=9.1,2.4 Hz, 1H), 6.89 (d, J=9.2 Hz, 1H), 4.59 (d, J=4.9 Hz, 2H), 3.80-3.68(m, 8H), 3.56 (s, 4H), 2.62 (t, J=6.4 Hz, 2H).

Example 555:6-[4-(3-[2-[(5-Bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of Int-A19 (170 mg, 0.28 mmol, 1 equiv) and TFA (0.7 mL) inDCM (7 mL) was stirred for 3 h at RT. The solvent was concentrated undervacuum and the residue was purified by C18 reverse phase chromatographyeluting with H₂O/ACN and then the residue was further purified byPrep-HPLC to afford the title compound (38.5 mg, 29%) as a white solid.LCMS [M+H]⁺ 477.31, ¹H NMR (300 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.47 (d,J=2.3 Hz, 1H), 8.05 (s, 1H), 7.85 (dd, J=9.1, 2.4 Hz, 1H), 6.89 (d,J=9.2 Hz, 1H), 4.44 (dd, J=5.2, 3.4 Hz, 2H), 3.77-3.57 (m, 8H),3.35-3.30 (m, 4H), 2.60 (t, J=6.5 Hz, 2H).

Example 556:5-[[(2R)-1-[3-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1:5-[[(2R)-1-Hydroxypropan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of Int-A6 (1 g, 3.04 mmol, 1.00 equiv),(2R)-2-aminopropan-1-ol (229 mg, 3.05 mmol, 1.00 equiv) and TEA (616 mg,6.09 mmol, 2.00 equiv) in EtOH (20 mL) was stirred for 1 h at 60° C. Theresulting solution was concentrated under vacuum, and the residue waspurified by silica gel column chromatography eluting withEtOAc/petroleum ether (1:1) to afford 1.03 g (92%) of title compound asa light brown oil. LCMS [M+H]⁺ 368.15.

Step 2: Methyl3-[(2R)-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate

A solution of5-[[(2R)-1-hydroxypropan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1 g, 2.72 mmol, 1.00 equiv), methyl prop-2-enoate (1.17 g, 0.01 mmol,5.00 equiv) and Cs₂CO₃ (2.65 g, 8.13 mmol, 3.00 equiv) in ACN (25 mL)was stirred for 3 h at RT. The solids were filtered and the resultingsolution was concentrated under vacuum, and the residue was purified bysilica gel column chromatography eluting with EtOAc/petroleum ether(3:7) to give 604 mg (49%) of title compound as a light brown oil. LCMS[M+H]⁺ 454.53.

Step 3: Methyl3-[(2R)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate

A solution of methyl3-[(2R)-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate(600 mg, 1.32 mmol, 1.00 equiv) and TFA (1.5 mL) in DCM (6 mL) wasstirred for 1 h at RT. The resulting solution was concentrated undervacuum, and the residue was dissolved in NH₃ (g) in MeOH (2 mL, 7M) andstirred for 15 min at RT. The resulting solution was concentrated undervacuum to afford 400 mg (94%) of title compound as a light brown oil.LCMS [M+H]⁺ 324.11.

Step 4: 3-[(2R)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-ylamino propoxy Propanoic Acid

A solution of methyl3-[(2R)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate(400 mg, 1.24 mmol, 1 equiv) and LiOH (148.2 mg, 6.19 mmol, 5.00 equiv)in MeOH (5 mL) and H₂O (1 mL) was stirred for 4 h at RT, and then the pHvalue of the solution was adjusted to 4 with HCl (1 M). The solid wascollected by filtration to afford 115 mg (30%) of title compound as ayellow solid. LCMS [M+H]⁺ 310.10.

Step 5:5-[[(2R)-1-[3-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of3-[(2R)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoicacid (115 mg, 0.37 mmol, 1 equiv), Int-A3 (73.9 mg, 0.37 mmol, 1.00equiv), HATU (141.4 mg, 0.37 mmol, 1.00 equiv) and DIPEA (96.1 mg, 0.74mmol, 2.00 equiv) in DMF (4 mL) was stirred for 40 min at RT, and thenthe resulting solution was diluted with 20 mL of H₂O, extracted with3×20 mL of EtOAc and the organic layer was combined, washed with 1×20 mLof brine and concentrated under vacuum. The residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN to afford the titlecompound as a white solid. LCMS [M+H]⁺ 490.05, ¹H NMR (300 MHz, DMSO-d6)δ 12.32 (s, 1H), 8.46 (d, J=5.7 Hz, 2H), 7.91 (s, 1H), 6.29 (dd, J=8.4,4.2 Hz, 1H), 4.19-4.10 (m, 1H), 3.74-3.62 (m, 6H), 3.53-3.48 (m, 6H),2.59 (t, J=6.5 Hz, 2H), 1.15 (d, J=6.5 Hz, 3H).

Example 557:5-[[(2R)-1-[3-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]-3-methoxypropan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1:(2R)-3-Methoxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propanoicAcid

A solution of (2R)-2-amino-3-methoxypropanoic acid hydrochloride (310mg, 1.99 mmol, 1.00 equiv), TEA (500 mg, 4.94 mmol, 2.00 equiv) andInt-A6 (800 mg, 2.43 mmol, 1.20 equiv) in EtOH (5 mL) was stirred for 1h at 60° C., and then the resulting solution was concentrated undervacuum to afford 1.2 g of crude title compound as a yellow oil. LCMS[M+H]⁺ 412.15.

Step 2:5-[[(2S)-1-Hydroxy-3-methoxypropan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of(2R)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propanoicacid (1.2 g, 2.92 mmol, 1.00 equiv) in BH₃-THF (1M, 20 mL) was stirredfor 1 h at RT, and then the resulting solution was quenched by theaddition of 100 mL of water, extracted with 3×100 mL of EtOAc and theorganic layers combined and concentrated under vacuum. The residue wasthen purified by C18 reverse phase chromatography eluting with H₂O/ACNto afford 840 mg (72%) of title compound as a yellow oil. LCMS [M+H]⁺398.17.

Step 3: Methyl3-[(2R)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoate

A solution of5-[[(2S)-1-hydroxy-3-methoxypropan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(800 mg, 2.01 mmol, 1.00 equiv), Cs₂CO₃ (1967.4 mg, 6.04 mmol, 3 equiv)and methyl prop-2-enoate (1732.8 mg, 20.13 mmol, 10 equiv) in ACN (10mL) was stirred for 2 h at RT, and then the solids were filtered. Theresulting solution was concentrated under vacuum, and the residue waspurified by silica gel column chromatography eluting withEtOAc/petroleum ether to afford 420 mg (43%) of title compound as ayellow oil. LCMS [M+H]⁺ 484.20.

Step 4: Methyl3-[(2R)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate

A solution of methyl3-[(2R)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate(400 mg, 0.83 mmol, 1 equiv) and TFA (1 mL) in DCM (5 mL) was stirredfor 1 h at RT, and then the resulting solution was concentrated undervacuum to afford 500 mg of title compound as a yellow crude oil. LCMS[M+H]⁺ 354.12.

Step 5: Methyl3-[(2R)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate

A solution of methyl3-[(2R)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate(500 mg, 1.42 mmol, 1 equiv) and LiOH (67.8 mg, 2.83 mmol, 2.00 equiv)in MeOH (10 mL) and H₂O (2 mL) was stirred for 2 h at RT, and then thepH of the resulting solution was adjusted to 5 with TFA and concentratedunder vacuum. The residue was purified by C18 reverse phasechromatography eluting with H₂O/ACN to afford 230 mg (48%) of titlecompound as a yellow oil. LCMS [M+H]⁺ 340.11.

Step 6:5-[[(2R)-1-[3-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]-3-methoxypropan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of3-[(2R)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoicacid (200 mg, 0.59 mmol, 1 equiv), DIPEA (152.4 mg, 1.18 mmol, 2 equiv),HATU (224.1 mg, 0.59 mmol, 1 equiv) and Int-A3 (117.1 mg, 0.59 mmol, 1equiv) in DMF (2 mL) was stirred for 1 h at RT, and then the resultingsolution was purified by C18 reverse phase chromatography eluting withH₂O/ACN. The residue was further purified by Prep-HPLC to afford thetitle compound (84.2 mg, 27%) as a white solid. LCMS [M+H]⁺ 520.10, ¹HNMR (300 MHz, Methanol-d₄) δ 8.33 (s, 2H), 7.97 (s, 1H), 4.21 (t, J=5.3Hz, 1H), 3.86-3.51 (m, 14H), 3.38 (s, 3H), 2.70 (t, J=6.0 Hz, 2H).

Example 558:5-[[(2S)-1-[3-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]-3-methoxypropan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: (2R)-2-Amino-3-methoxypropan-1-ol

A solution of (2S)-2-amino-3-methoxypropanoic acid (2 g, 16.79 mmol, 1equiv) in BH₃-THF (20 mL, 1M) was stirred for 1 h at RT upon which thereaction was quenched with MeOH (20 mL). The resulting solution wasconcentrated under vacuum to afford 2.2 g of title compound as acolorless crude oil. LCMS [M+H]⁺ 106.08.

Step 2:5-[[(2R)-1-Hydroxy-3-methoxypropan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of (2R)-2-amino-3-methoxypropan-1-ol (500 mg, 4.76 mmol, 1equiv), TEA (962.5 mg, 9.51 mmol, 2.0 equiv) and Int-A6 (1560 mg, 4.74mmol, 1.00 equiv) in EtOH (10 mL) was stirred for 1 h at 60° C. Theresulting solution was concentrated under vacuum, and then the residuewas purified by silica gel column chromatography eluting withEtOAc/petroleum ether (1/1) to afford 850 mg (45%) of title compound asa yellow oil. LCMS [M+H]⁺ 398.17.

Step 3: Methyl3-[(2S)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate

A solution of5-[[(2R)-1-hydroxy-3-methoxypropan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(800 mg, 2.01 mmol, 1 equiv), Cs₂CO₃ (1967.4 mg, 6.04 mmol, 3 equiv) andmethyl prop-2-enoate (1732.8 mg, 20.13 mmol, 10 equiv) in ACN (10 mL)was stirred for 2h at RT. The solids were filtered and the resultingsolution was concentrated under reduced pressure. The residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether toafford 620 mg (64%) of title compound as a yellow oil. LCMS [M+H]⁺484.20.

Step 4: Methyl3-[(2S)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate

A solution of methyl3-[(2S)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate(600 mg, 1.24 mmol, 1 equiv) and TFA (1 mL) in DCM (5 mL) was stirredfor 1 h at RT and then the resulting solution was concentrated undervacuum to afford 650 mg of title compound as a yellow oil. LCMS [M+H]⁺354.12.

Step 5:3-[(2S)-3-Methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoicAcid

A solution of methyl3-[(2S)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate(600 mg, 1.70 mmol, 1 equiv) and LiOH (406.7 mg, 16.98 mmol, 10 equiv)in MeOH (10 mL) and H₂O (2 mL) was stirred for 2h at RT, and then theresulting solution was concentrated under vacuum and the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN toafford 260 mg (45%) of title compound as a yellow oil. LCMS [M+H]⁺340.11.

Step 6:5-[[(2S)-1-[3-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]-3-methoxypropan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of3-[(2S)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoicacid (250 mg, 0.74 mmol, 1 equiv), HATU (280.2 mg, 0.74 mmol, 1.0equiv), DIPEA (190.5 mg, 1.47 mmol, 2.0 equiv) and Int-A3 (146.4 mg,0.74 mmol, 1 equiv) in DMF (2 mL) was stirred for 1 h at RT, and thenthe resulting solution was purified by C18 reverse phase chromatographyeluting with H₂O/ACN. The residue was further purified by Prep-HPLC toafford the title compound (121 mg, 32%) as a white solid. LCMS [M+H]⁺520.05. ¹H NMR (300 MHz, Methanol-d₄) δ 8.33 (s, 2H), 7.96 (s, 1H), 4.21(t, J=5.3 Hz, 1H), 3.84-3.55 (m, 14H), 3.38 (s, 3H), 2.72 (t, J=6.0 Hz,2H).

Example 559:5-[[(2S)-1-Methoxy-3-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of3-[(2S)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoicacid (Example 558, Step 5; 100 mg, 0.29 mmol, 1 equiv), HATU (112.1 mg,0.29 mmol, 1.0 equiv), Int-A2 (68.4 mg, 0.29 mmol, 1 equiv) and DIPEA(76.2 mg, 0.59 mmol, 2.0 equiv) in DMF (2 mL) was stirred for 1 h at RT.The resulting solution was purified by C18 reverse phase chromatographyeluting with H₂O/ACN which after concentrated under reduced pressure.The residue was further purified by Prep-HPLC to afford the titlecompound (56.7 mg, 35%) as a white solid. LCMS [M+H]⁺ 554.30. ¹H NMR(300 MHz, Methanol-d4) δ 8.61 (d, J=0.9 Hz, 2H), 7.98 (s, 1H), 4.23 (t,J=5.1 Hz, 1H), 3.98-3.60 (m, 12H), 3.59-3.52 (m, 2H) 3.39 (s, 3H), 2.71(t, J=5.9 Hz, 2H).

Example 560 Isomer A:5-[(2S)-2-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]-3-methoxypropoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand Example 560 Isomer B:5-[(2R)-2-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]-3-methoxypropoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand Example 560 Isomer C:5-[[(2S)-1-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]-3-methoxypropan-2-yl]oxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Mixture of1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-(2-hydroxy-3-methoxypropoxy)propan-1-oneand1-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-((1-hydroxy-3-methoxypropan-2-yl)oxy)propan-1-one

A solution of Int-A23 (1 g, 3.96 mmol, 1 equiv),3-methoxypropane-1,2-diol (5.0 g, 0.05 mmol, 12 equiv) and Cs₂CO₃ (2.6g, 0.01 mmol, 2.0 equiv) in ACN (30 mL) was stirred for 15 h at 70° C.,and then the solids were filtered and the resulting solution wasconcentrated under reduced pressure. The residue was purified by C18reverse phase chromatography eluting with H₂O/ACN to afford 800 mg (56%)of the mixture of the title compounds as a white oil. LCMS: [M+H]⁺359.14.

Step 2: Mixture of5-((1-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)-3-methoxypropan-2-yl)oxy)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-oneand5-(2-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)-3-methoxypropoxy)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(6H)-one

A mixture of1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-(2-hydroxy-3-methoxypropoxy)propan-1-oneand1-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-((1-hydroxy-3-methoxypropan-2-yl)oxy)propan-1-one(0.72 g, 2.01 mmol, 1 equiv), Cs₂CO₃ (0.98 g, 3.01 mmol, 1.50 equiv) andInt-A6 (2.4 g, 7.30 mmol, 3.64 equiv) in ACN (15 mL) was stirred for 4 hat 80° C., and then the solids were filtered out and the resultingsolution was concentrated under reduced pressure. The residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether toafford 420 mg (32%) of the mixture of title compounds as a yellow oil.LCMS: [M+H]⁺ 651.15.

Step 3: Isomer A:5-[(2S)-2-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]-3-methoxypropoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand Isomer B:5-[(2R)-2-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]-3-methoxypropoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand Isomer C:5-[[(2S)-1-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]-3-methoxypropan-2-yl]oxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand Isomer D:5-[[(2R)-1-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]-3-methoxypropan-2-yl]oxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A mixture of5-((1-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)-3-methoxypropan-2-yl)oxy)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-oneand5-(2-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)-3-methoxypropoxy)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(6H)-one (400 mg, 0.61 mmol, 1 equiv) and TFA (2 mL) in DCM (10 mL) wasstirred for 1 h at RT, and then the resulting mixture was concentratedunder reduced pressure. The residue was purified by C18 reverse phasechromatography eluting with H₂O/ACN, and then the residue was furtherpurified by Prep-HPLC and Chiral-Prep-HPLC. The absolute stereochemistryof Example 560 Isomer A and Example 560 Isomer B was assigned based on aprotein X-ray crystal structure obtained of Example 513A, whichconfirmed (S)-absolute stereochemistry of the more potent enantiomer.The stereochemistry of Examples 560 Isomers C and D was arbitrarilyassigned. (The position of the methyl group was confirmed by ¹H-NMR).

Example 560 Isomers A and B: Chiral-Prep-HPLC (CHIRALPAK IE-3, 3 μm,0.46×10 cm column, eluting with a gradient of MtBE (0.1%DEA):EtOH=90:10, at a flow rate of 1 mL/min) to afford the titlecompounds as white solids.

Example 560 Isomer A

LCMS: [M+H]⁺ 521.05, ¹H NMR (300 MHz, DMSO-d₆) δ 13.23 (s, 1H), 8.45 (d,J=5.7 Hz, 2H), 8.27 (s, 1H), 5.18 (dd, J=6.3, 3.0 Hz, 1H), 3.74-3.50 (m,14H), 3.31 (s, 3H), 2.57 (t, J=6.4 Hz, 2H). tR=3.682 min.

Example 560 Isomer B

LCMS: [M+H]⁺ 521.05, ¹H NMR (300 MHz, DMSO-d₆) δ 13.23 (s, 1H), 8.46 (d,J=5.7 Hz, 2H), 8.28 (s, 1H), 5.18 (dd, J=6.6, 3.5 Hz, 1H), 3.74-3.49 (m,14H), 3.31 (s, 3H), 2.56 (t, J=6.5 Hz, 2H). tR=8.735 min.

Example 560 Isomers C and D: Chiral-Prep-HPLC (CHIRALPAK IG-3, 3 μm,0.46×10 cm column, eluting with a gradient of MtBE (0.1%DEA):EtOH=70:30, at a flow rate of 1 mL/min) to afford the titlecompounds as white solids.

Example 560 Isomer C

LCMS: [M+H]⁺ 521.05, ¹H NMR (300 MHz, DMSO-d₆) δ 13.31 (s, 1H), 8.46 (d,J=5.7 Hz, 2H), 8.24 (s, 1H), 4.52 (dd, J=10.7, 3.7 Hz, 1H), 4.42 (dd,J=10.7, 5.6 Hz, 1H), 3.81-3.65 (m, 11H), 3.45 (d, J=5.2 Hz, 2H), 3.31(s, 3H), 2.58 (t, J=6.6 Hz, 2H). tR=2.653 min.

Example 560 Isomer D

LCMS: [M+H]⁺ 521.05, ¹H NMR (300 MHz, DMSO-d₆) δ 13.31 (s, 1H), 8.47 (d,J=5.7 Hz, 2H), 8.25 (s, 1H), 4.53 (dd, J=10.7, 3.7 Hz, 1H), 4.46-4.32(m, 1H), 3.83-3.63 (m, 7H), 3.53-3.46 (m, 4H), 3.45 (d, J=5.1 Hz, 2H),3.30 (s, 3H), 2.59 (t, J=6.7 Hz, 2H). tR=3.471 min.

Example 561:5-[[(2S)-1-(3-Oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of Int-A13 (150 mg, 0.485 mmol, 1 equiv), HATU (184 mg, 0.484mmol, 1 equiv), DIPEA (0.32 mL, 2 mmol, 4 equiv), and Int-A2 (148 mg,0.487 mmol, 1 equiv) in DMF (2 mL) was stirred for 0.5 h at 25° C. Tothe resulting mixture was added ethanolamine (0.5 mL) and the reactionmixture was stirred for 0.5 h at 25° C. After concentration underreduced pressure, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford the title compound (50.7mg, 20%) as a white solid. LCMS: [M+H]⁺ 524.20, ¹H NMR (300 MHz,DMSO-d₆) δ: 12.45 (s, 1H), 8.73 (s, 2H), 7.92 (s, 1H), 6.28 (dd, J=8.5,4.2 Hz, 1H), 4.13-4.18 (m, 1H), 3.90-3.75 (m, 4H), 3.63-3.73 (m, 2H),3.60-3.45 (m, 6H), 2.60 (t, J=6.6 Hz, 2H), 1.16 (d, J=6.1 Hz, 3H).

Example 561 was also prepared according to the procedure outlined below.

Step 1:1-(4-(5-Trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-2-en-1-one

A solution of Int-A2 (300 g, 1.1 mol, 1 equiv), prop-2-enoylprop-2-enoate (156 g, 1.24 mol, 1.1 equiv) and TEA (375 g, 3.71 mol, 3.3equiv) in DCM (2.5 L) was stirred for 30 min at −40° C. 2 L of DCM wasadded to the resulting solution after the reaction completed and theresulting solution was extracted with 2×1 L of water. The organic layerwas concentrated and the residue was applied onto a silica gel columneluting with EtOAc/petroleum ether (1/4). The collected fractions werecombined and concentrated to afford 200 g (62.6%) of title compound as awhite solid. LCMS: [M+H]⁺ 287.23.

Step 2: (S)-Tert-butyl1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-ylcarbamate

A solution of tert-butyl N-[(2S)-1-hydroxypropan-2-yl]carbamate (244 g,1.39 mol, 2 equiv),1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-2-en-1-one(200 g, 699 mmol, 1 equiv), and Cs₂CO₃ (273 g, 838 mmol, 1.2 equiv) inCH₃CN (1.4 L) was stirred for 24 h at 25° C. The solids were filteredand the filtrate was concentrated under reduced pressure. The residuewas applied onto a silica gel column eluting with EtOAc/petroleum ether(1/3) to afford 257 g (80%) of title compound as a white solid. LCMS:[M+H]⁺ 462.27.

Step 3:(S)-3-(2-Aminopropoxy)-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propan-1-one

A solution of1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-2-en-1-one(257 g, 557 mmol, 1 equiv) and dioxane/HCl (4 mol/L, 1 L) was stirredfor 2 h at 25° C. The pH value of the reaction mixture was adjusted to 7by the addition of NaOH (aqueous). After concentration under reducedpressure, the residue was purified by C18 reverse phase chromatographyeluting with H₂O/CH₃CN to afford 167 g (83.0%) of title compound as awhite solid. LCMS: [M+H]⁺ 362.34.

Step 4:(S)-2-(4-Methoxybenzyl)-5-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of(S)-3-(2-aminopropoxy)-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propan-1-one(167 g, 462 mmol, 1 equiv), Int-A20 (161 g, 505 mmol, 1.1 equiv), andTEA (210 g, 2.08 mol, 4.5 equiv) in CH₃CN (1.2 L) was stirred for 6 h at25° C. The solids were filtered and the filtrate was combined andconcentrated under reduced pressure. The residue was applied onto asilica gel column with EtOAc/petroleum ether (1/1) to afford 230 g(77.3%) of title compound as a white solid. LCMS: [M+H]⁺ 644.41.

Step 5:5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of(S)-2-(4-methoxybenzyl)-5-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(2H)-one(230 g, 358 mmol, 1 equiv) and TfOH (115 mL) in TFA (1.0 L) was stirredfor 2 h at 25° C. The reaction was then quenched by the addition of 4.0L of water. The resulting solution was extracted with 2×1 L of EtOAc.The pH value of the organic layers was adjusted to 8 by aqueous K₂CO₃solution. The organic layer was combined and concentrated. The residuewas applied onto a silica gel column with EtOAc/petroleum ether (4/1).The fractions were combined and concentrated followed by further washingwith EtOAc to afford 114 g (61.2%) of title compound as a whitecrystalline solid. LCMS: [M+H]⁺ 524.25[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆)δ: 12.45 (s, 1H), 8.73 (s, 2H), 7.91 (s, 1H), 6.29-6.26 (m, 1H),4.12-4.19 (m, 1H), 3.81-3.85 (m, 4H), 3.73-3.79 (m, 2H), 3.54-3.69 (m,6H), 2.60 (t, J=9.2 Hz, 2H), 1.16 (d, J=12.4 Hz, 3H).

Characterization of crystalline5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(Form A)

The solid product from Step 5 was confirmed as a crystalline solidaccording to XRPD analysis. The XRPD pattern of crystalline5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one(“Compound 561 Form A” or “Form A”) is shown in FIG. 8 and the peak datais given below in Table X1.

TABLE X1 XRPD Peak Data for Form A. FWHM Left Pos. [°2Th.] Height [cts][°2Th.] d-spacing [A] Rel. Int. [%] 5.8 929.0 0.1 15.4 33.0 10.8 932.80.1 8.2 33.1 11.2 202.2 0.1 7.9 7.2 11.9 791.4 0.2 7.5 28.1 12.3 213.60.1 7.2 7.6 13.3 515.1 0.1 6.7 18.3 13.5 437.1 0.1 6.6 15.5 13.8 172.10.1 6.4 6.1 15.5 541.5 0.1 5.7 19.2 15.8 270.0 0.1 5.6 9.6 16.6 127.70.1 5.4 4.5 17.2 2814.9 0.1 5.1 100.0 17.7 645.6 0.1 5.0 22.9 18.0 611.50.1 4.9 21.7 18.4 417.5 0.1 4.8 14.8 18.7 163.9 0.1 4.7 5.8 19.5 604.90.1 4.5 21.5 20.1 278.7 0.1 4.4 9.9 20.5 506.0 0.1 4.3 18.0 21.0 1121.60.1 4.2 39.9 21.6 2094.1 0.1 4.1 74.4 21.8 1357.3 0.1 4.1 48.2 22.1851.6 0.1 4.0 30.3 22.4 613.7 0.1 4.0 21.8 22.7 1295.5 0.1 3.9 46.0 23.02760.9 0.1 3.9 98.1 23.4 1332.8 0.1 3.8 47.4 24.2 379.7 0.1 3.7 13.524.7 349.2 0.2 3.6 12.4 24.9 1343.4 0.1 3.6 47.7 25.5 125.9 0.1 3.5 4.526.2 113.9 0.1 3.4 4.1 26.7 449.2 0.1 3.3 16.0 27.5 93.8 0.2 3.2 3.328.0 176.1 0.1 3.2 6.3 28.7 136.0 0.2 3.1 4.8 30.8 272.1 0.1 2.9 9.731.4 138.3 0.3 2.8 4.9 32.7 79.4 0.2 2.7 2.8 36.5 40.6 0.3 2.5 1.4

Form A exhibits a DSC thermogram having an endotherm peak at atemperature of about 174° C. Form A shows a weight loss of about 0.5%when heated to 150° C. FIG. 9 shows a DSC thermogram and a TGAthermogram of Compound 561 Form A. FIG. 10 shows a DVS isotherm ofCompound 561 Form A. The data suggest that Form A may be an anhydrouscrystalline form.

The following examples in Table E9 were similarly prepared according tothe method described for Example 561.

TABLE E9 Example Name, structure, analytical data Int. Example 562

Int-A13 and Int-A35-[[(2S)-1-[3-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one; LCMS: [M + H]⁺ 490.0; ¹H NMR (400 MHz,Methanol-d₄) δ 8.33 (s, 2H), 7.95 (s, 1H), 4.17 (q, J = 6.1 Hz, 1H),3.89-3.75 (m, 6H), 3.78-3.57 (m, 5H), 3.52 (dd, J = 9.7, 6.8 Hz, 1H),2.71 (t, J = 6.0 Hz, 2H), 1.27 (d, J = 6.6 Hz, 3H). Example 563

Int-A13 and Int-A55-[[(2S)-1-[3-[4-(5-Chloropyridin-2-yl)piperazin-1-yl]-3-oxopropoxy]propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one; LCMS: [M + H]⁺ 489.35; ¹HNMR (400 MHz,Methanol-d₄) δ: 8.08 (d, J = 2.4 Hz, 1H), 7.95 (s, 1H), 7.55 (dd, J =9.1, 2.7 Hz, 1H), 6.81 (d, J = 9.1, 1H), 4.20- 4.10 (m, 1H), 3.90-3.69(m, 2H), 3.74-3.51 (m, 4H), 3.49-3.37 (m, 6H), 2.70 (t, J = 6.0 Hz, 2H),1.27 (d, J = 6.6 Hz, 3H). Example 564

Int-A13 and Int-A185-[[(2S)-1-(3-Oxo-3-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one; LCMS: [M + H]⁺ 523.30; ¹H NMR (300 MHz,Methanol-d₄) δ 8.36 (s, 1H), 7.93 (s, 1H), 7.74 (dd, J = 9.1, 2.5 Hz,1H), 6.87 (d, J = 9.1 Hz, 1H), 4.20- 4.14 (m, 1H), 3.85-3.80 (m, 2H),3.78-3.68 (m, 8H), 3.61 (dd, J = 9.7, 4.0 Hz, 1H), 3.49 (dd, J = 9.7,6.8 Hz, 1H), 2.68 (t, J = 6.0 Hz, 2H), 1.25 (d, J = 6.6 Hz, 3H).

Example 565 Isomer A:5-[[(2S,5S)-5-[2-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand Example 565 Isomer B:5-[[(2R,5R)-5-[2-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand Example 565 Isomer C:5-[[(2S,5R)-5-[2-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand Example 565 Isomer D:5-[[(2R,5S)-5-[2-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1:2-[5-[(Benzyloxy)methyl]oxolan-2-yl]-1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]ethan-1-one

A solution of 2-[5-[(benzyloxy)methyl]oxolan-2-yl]acetic acid (2 g, 7.99mmol, 1 equiv), HATU (3949.7 mg, 10.39 mmol, 1.3 equiv), DIPEA (4130.9mg, 31.96 mmol, 4 equiv), and Int-A3 (1587.3 mg, 7.99 mmol, 1 equiv) inDMF (25 mL) was stirred for 1.5 h at RT. After concentration underreduced pressure, the residue was purified by C18 reverse phasechromatography eluting with H₂O/ACN to afford 2.6 g (76%) of the titlecompound as a yellow oil. LCMS: [M+H]⁺ 431.18.

Step 2:1-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-2-[5-(hydroxymethyl)oxolan-2-yl]ethan-1-one

A solution of2-[5-[(benzyloxy)methyl]oxolan-2-yl]-1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]ethan-1-one(2.17 g, 5 mmol, 1 equiv), TMSI (5 g, 25 mmol, 5.00 equiv) in DCM (20mL) was stirred overnight at 40° C. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/ACN toafford 1.6 g (94%) of the title compound as a yellow solid. LCMS: [M+H]⁺341.14.

Step 3: Methyl5-[(5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl)methoxy]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-[5-(hydroxymethyl)oxolan-2-yl]ethan-1-one(800 mg, 2.35 mmol, 1 equiv), Cs₂CO₃ (2294.4 mg, 7.04 mmol, 3 equiv),Int-A6 (1543.6 mg, 4.69 mmol, 2.00 equiv) in DMF (20 mL) was stirred for3 h at 80° C. The solids were filtered and the resulting solution wasquenched with water (50 mL) and extracted with EtOAc (3×60 mL) and theorganic layers combined. The solution was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column with EtOAc/petroleum ether (1:1) to afford 600 mg(40%) of the title compound as a yellow solid. LCMS: [M+H]⁺ 633.22.

Step 4:5-[[(2S,5S)-5-[2-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one,5-[[(2R,5R)-5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one,5-[[(2S,5R)-5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand5-[[(2R,5S)-5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[(5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl)methoxy]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(600 mg, 0.95 mmol, 1 equiv) and TFA (4 mL) in DCM (20 mL) was stirredfor 1 h at RT. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/ACN. The residue wasfurther purified by Prep-HPLC and Chiral-Prep-HPLC (CHIRALPAK IA-3, 3μm, 0.46×5 cm column, eluting with a gradient of MtBE (10 mMNH₃):IPA=85:15, at a flow rate of 1 mL/min) yielding (after arbitraryassignment of absolute stereochemistry) the title compounds as whitesolids.

Example 565 Isomer A

46.5 mg, 10%, LCMS: [M+H]⁺ 503.20, ¹H NMR (300 MHz, Methanol-d₄) δ 8.29(s, 2H), 8.22 (s, 1H), 4.54 (dd, J=10.7, 3.1 Hz, 1H), 4.41-4.24 (m, 3H),3.90-3.74 (m, 2H), 3.73-3.58 (m, 4H), 3.56-3.53 (m, 2H), 2.76 (dd,J=14.8, 7.8 Hz, 1H), 2.55 (dd, J=14.8, 4.8 Hz, 1H), 2.15-2.06 (m, 2H),1.96-1.92 (m, 1H), 1.80-1.68 (m, 1H). tR=1.725 min.

Example 565 Isomer B

46.3 mg, 10%, LCMS: [M+H]⁺ 503.20, ¹H NMR (300 MHz, Methanol-d₄) δ 8.29(s, 2H), 8.20 (s, 1H), 4.46-4.33 (m, 4H), 3.90-3.56 (m, 8H), 2.80 (dd,J=14.8, 7.8 Hz, 1H), 2.55 (dd, J=14.8, 4.8 Hz, 1H), 2.24-2.18 (m, 2H),1.89-1.76 (m, 1H), 1.73-1.72 (m, 1H). tR=2.396 min.

Example 565 Isomer C

34.5 mg 7%, LCMS: [M+H]⁺ 503.20, ¹H NMR (300 MHz, Methanol-d₄) δ 8.29(s, 2H), 8.20 (s, 1H), 4.46-4.33 (m, 4H), 3.90-3.54 (m, 8H), 2.80 (dd,J=14.8, 7.8 Hz, 1H), 2.55 (dd, J=14.8, 4.8 Hz, 1H), 2.24-2.17 (m, 2H),1.89-1.76 (m, 1H), 1.73-1.72 (m, 1H). tR=3.189 min.

Example 565 Isomer D

35.2 mg 7%, LCMS: [M+H]⁺ 503.20, ¹H NMR (300 MHz, Methanol-d₄) δ 8.29(s, 2H), 8.22 (s, 1H), 4.54 (dd, J=10.7, 3.1 Hz, 1H), 4.41-4.24 (m, 3H),3.90-3.74 (m, 2H), 3.73-3.58 (m, 4H), 3.56-3.55 (m, 2H), 2.76 (dd,J=14.8, 7.8 Hz, 1H), 2.55 (dd, J=14.8, 4.8 Hz, 1H), 2.17-2.06 (m, 2H),1.96-1.92 (m, 1H), 1.80-1.68 (m, 1H). tR=3.805 min.

Example 566 Isomer A:4-Chloro-5-[[(2S,5S)-5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]methoxy]-2,3-dihydropyridazin-3-oneand Example 566 Isomer B:4-Chloro-5-[[(2R,5R)-5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]methoxy]-2,3-dihydropyridazin-3-oneExample 566 Isomer C:4-Chloro-5-[[(2S,5R)-5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]methoxy]-2,3-dihydropyridazin-3-oneand Example 566 Isomer D:4-Chloro-5-[[(2R,5S)-5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]methoxy]-2,3-dihydropyridazin-3-one

Step 1:4-Chloro-5-[(5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl)methoxy]-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-[5-(hydroxymethyl)oxolan-2-yl]ethan-1-one(840 mg, 2.46 mmol, 1 equiv), NaH (118.3 mg, 4.93 mmol, 2 equiv), andInt-A7 (2183.0 mg, 7.39 mmol, 3.00 equiv) in ACN (20 mL) was stirred for1.5 h at RT. The solvent was concentrated under reduced pressure and theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1:1) to afford 850 mg (58%) of the title compoundas a yellow oil. LCMS: [M+H]⁺ 599.20.

Step 2:4-Chloro-5-[[(2S,5S)-5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]methoxy]-2,3-dihydropyridazin-3-one,4-chloro-5-[[(2S,5R)-5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]methoxy]-2,3-dihydropyridazin-3-one,4-chloro-5-[[(2R,5R)-5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]methoxy]-2,3-dihydropyridazin-3-oneand4-chloro-5-[[(2R,5S)-5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl]methoxy]-2,3-dihydropyridazin-3-one

A solution of4-chloro-5-[(5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl)methoxy]-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(800 mg, 1.33 mmol, 1 equiv) and TFA (4 mL) in DCM (20 mL) was stirredfor 1 h at RT. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/ACN. The residue wasfurther purified by Prep-HPLC and Chiral-Prep-HPLC (CHIRALPAK IA-3, 3μm, 0.46×15 cm column, eluting with a gradient of MtBE (0.3%isopropylamine):IPA=75:25, at a flow rate of 1 mL/min) yielding (afterarbitrary assignment of absolute stereochemistry) the title compounds aswhite solids.

Example 566 Isomer A

49.1 mg, 8%, LCMS: [M+H]⁺ 469.10, ¹H NMR (300 MHz, Methanol-d₄) δ 8.28(s, 2H), 8.15 (s, 1H), 4.51-4.47 (m, 1H), 4.35-4.28 (m, 3H), 3.86-3.62(m, 6H), 3.58-3.51 (m, 2H), 2.79 (dd, J=14.7, 7.9 Hz, 1H), 2.56 (dd,J=14.7, 4.7 Hz, 1H), 2.18-2.11 (m, 2H), 2.00-1.98 (m, 1H), 1.96-1.95 (m,1H); tR=2.184 min.

Example 566 Isomer B

66.9 mg, 11%, LCMS: [M+H]⁺ 469.15, ¹H NMR (300 MHz, Methanol-d₄) δ 8.28(s, 2H), 8.14 (s, 1H), 4.43-4.31 (m, 4H), 3.94-3.60 (m, 5H), 3.58-3.51(m, 3H), 2.79 (dd, J=14.7, 7.9 Hz, 1H), 2.56 (dd, J=14.7, 4.7 Hz, 1H),2.24-2.17 (m, 2H), 1.89-1.85 (m, 1H), 1.77-1.74 (m, 1H). tR=3.458 min

Example 566 Isomer C

47.7 mg, 8%, LCMS: [M+H]⁺ 469.10, ¹H NMR (300 MHz, Methanol-d₄) δ 8.28(s, 2H), 8.15 (s, 1H), 4.51-4.47 (m, 1H), 4.35-4.28 (m, 3H), 3.86-3.62(m, 6H), 3.58-3.51 (m, 2H), 2.79 (dd, J=14.7, 7.9 Hz, 1H), 2.56 (dd,J=14.7, 4.7 Hz, 1H), 2.18-2.11 (m, 2H), 2.00-1.98 (m, 1H), 1.96-1.95 (m,1H). tR=4.325 min

Example 566 Isomer D

37.0 mg, 6%, LCMS: [M+H]⁺ 469.10, ¹H NMR (300 MHz, Methanol-d₄) δ 8.31(s, 2H), 8.14 (s, 1H), 4.44-4.31 (m, 4H), 3.94-3.85 (m, 2H), 3.79-3.52(m, 6H), 2.79 (dd, J=14.7, 7.9 Hz, 1H), 2.56 (dd, J=14.7, 4.7 Hz, 1H),2.26-2.20 (m, 2H), 1.89-1.85 (m, 1H), 1.77-1.74 (m, 1H). tR=5.695 min.

Example 567 Isomer A:5-((((2S,5R)-5-(2-(4-(5-Chloropyrimidin-2-yl)piperazin-1-yl)-2-oxoethyl)tetrahydrofuran-2-yl)methyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-oneand Example 567 Isomer B:5-((((2R,5S)-5-(2-(4-(5-Chloropyrimidin-2-yl)piperazin-1-yl)-2-oxoethyl)tetrahydrofuran-2-yl)methyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-oneExample 567 Isomer C:5-((((2S,5S)-5-(2-(4-(5-Chloropyrimidin-2-yl)piperazin-1-yl)-2-oxoethyl)tetrahydrofuran-2-yl)methyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-oneand Example 567 Isomer D:5-((((2R,5R)-5-(2-(4-(5-Chloropyrimidin-2-yl)piperazin-1-yl)-2-oxoethyl)tetrahydrofuran-2-yl)methyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

Step 1:(5-[2-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl)methylmethanesulfonate

A solution of1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-[5-(hydroxymethyl)oxolan-2-yl]ethan-1-one(1 g, 2.93 mmol, 1 equiv), TEA (890.7 mg, 8.80 mmol, 3 equiv), andmethanesulfonyl methanesulfonate (766.7 mg, 4.40 mmol, 1.5 equiv) in DCM(20 mL) was stirred for 1 h at 25° C. To the resulting solution wasadded 20 mL of aqueous NaHCO₃, and the resulting solution was extractedwith 3×20 mL of DCM and the organic layers combined. The resultingsolution was washed with 20 mL of NH₄Cl(aq) and the organic layers werecombined and dried over anhydrous sodium sulfate and concentrated undervacuum to afford 1.1 g (90%) of the title compound as a yellow oil.LCMS: [M+H]⁺ 419.11.

Step 2:2-[5-(Azidomethyl)oxolan-2-yl]-1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]ethan-1-one

A solution of(5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl)methylmethanesulfonate (1.1 g, 2.63 mmol, 1 equiv), and NaN₃ (0.2 g, 3.15mmol, 1.2 equiv) in DMF (20 mL) was stirred for 4 h at 90° C. Theresulting solution was diluted with 30 mL of water and extracted with3×20 mL of EtOAc. The organic layers were combined and the resultingsolution was washed with 3×20 mL of saturated sodium chloride, driedover anhydrous sodium sulfate and concentrated to afford 600 mg (62%) ofthe title compound as a yellow oil. LCMS: [M+H]⁺ 366.14.

Step 3:2-[5-(Aminomethyl)oxolan-2-yl]-1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]ethan-1-one

A solution of2-[5-(azidomethyl)oxolan-2-yl]-1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]ethan-1-one(500 mg, 1.37 mmol, 1 equiv) and triphenylphosphine (537.7 mg, 2.05mmol, 1.5 equiv) in THF (20 mL) and H₂O (5 mL) was stirred 5 h at 60° C.After concentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/ACN to afford 450 mg (97%) of the titlecompound as a yellow oil. LCMS: [M+H]⁺ 340.15.

Step 4:5-[[(5-[2-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl)methyl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of2-[5-(aminomethyl)oxolan-2-yl]-1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]ethan-1-one(300 mg, 0.88 mmol, 1 equiv), Int-A6 (348.3 mg, 1.06 mmol, 1.2 equiv),and TEA (268.0 mg, 2.65 mmol, 3 equiv) in EtOH (20 mL) was stirred for 2h at 60° C. The solvent was concentrated under vacuum and the residuewas applied onto a silica gel column eluting with EtOAc/petroleum ether(1/1) to afford 480 mg (86%) of the title compound as a yellow oil.LCMS: [M+H]⁺ 632.23.

Step 5:5-((((2S,5R)-5-(2-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-2-oxoethyl)tetrahydrofuran-2-yl)methyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one,5-((((2R,5S)-5-(2-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-2-oxoethyl)tetrahydrofuran-2-yl)methyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one,5-((((2S,5S)-5-(2-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-2-oxoethyl)tetrahydrofuran-2-yl)methyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-oneand5-((((2R,5R)-5-(2-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-2-oxoethyl)tetrahydrofuran-2-yl)methyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of5-[[(5-[2-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl)methyl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(470 mg, 0.74 mmol, 1 equiv) and TFA (2 mL) in DCM (10 mL) was stirredfor 2 h at 25° C. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/ACN. The residue wasfurther purified by Prep-HPLC and Chiral-Prep-HPLC yielding (afterarbitrary assignment of the stereochemistry), the title compounds aswhite solids.

Chiral-Prep-HPLC purification of Isomer A and D by Repaired IA, 5 μm,0.46×10 cm column, eluting with a gradient of (Hexanes/DCM=3:1)(0.1%DEA):EtOH=95:5, at a flow rate of 1 mL/min). Chiral Prep-HPLCpurification of Isomer B and C by CHIRALPAK IG-3, 3 μm, 0.46×10 cmcolumn, eluting with a gradient of (Hexanes/DCM=1:1)(0.1%DEA):MeOH=50:50, at a flow rate of 1 mL/min).

Example 567 Isomer A

41.6 mg, 11%, LCMS: [M+H]⁺ 502.15, ¹H NMR (300 MHz, DMSO-d₆) δ 12.39 (s,1H), 8.43 (s, 2H), 7.91 (s, 1H), 6.92 (s, 1H), 4.21-4.10 (m, 1H), 3.97(s, 1H), 3.77-3.61 (m, 4H), 3.61-3.33 (m, 6H), 2.58 (dd, J=15.4, 6.4 Hz,1H), 2.37 (dd, J=15.4, 6.4 Hz, 1H), 2.09-1.83 (m, 2H), 1.68 (s, 1H),1.52 (d, J=10.5 Hz, 1H). tR=4.364 min

Example 567 Isomer B

(42.3 mg, 11.34%), LCMS: [M+H]⁺: 502.15, ¹H NMR (300 MHz, DMSO-d₆) 12.35(s, 1H), 8.41 (s, 2H), 7.88 (s, 1H), 6.91 (s, 1H), 4.23 (s, 1H), 4.08(s, 1H), 3.71 (m, 10H), 2.64 (d, J=7.1 Hz, 1H), 2.45 (d, 1H), 2.03 (d,J=29.9 Hz, 2H), 1.56 (s, 2H). tR=1.333 min.

Example 567 Isomer C

42.2 mg, 11%, LCMS: [M+H]⁺ 502.15, ¹H NMR (300 MHz, DMSO-d₆) δ 12.35 (s,1H), 8.41 (s, 2H), 7.88 (s, 1H), 6.99-6.81 (m, 1H), 4.25 (q, J=6.4 Hz,1H), 4.08 (t, J=5.9 Hz, 1H), 3.78-3.38 (m, 10H), 2.66 (dd, J=15.0, 6.6Hz, 1H), 2.42 (dd, J=14.9, 6.2 Hz, 1H), 2.12-1.91 (m, 2H), 1.68-1.47 (m,2H). tR=1.719 min.

Example 567 Isomer D

31.8 mg, 9%, LCMS: [M+H]⁺ 502.15, ¹H NMR (300 MHz, DMSO-d₆) δ 12.39 (s,1H), 8.43 (s, 2H), 7.91 (s, 1H), 6.93 (s, 1H), 4.15 (q, J=6.5 Hz, 1H),3.97 (s, 1H), 3.77-3.61 (m, 4H), 3.61-3.33 (m, 6H), 2.58 (dd, J=15.4,6.5 Hz, 1H), 2.37 (dd, J=15.3, 6.3 Hz, 1H), 2.07-1.80 (m, 2H), 1.65 (dd,J=12.7, 6.2 Hz, 1H), 1.58-1.42 (m, 1H). tR=6.678 min.

Example 568 Isomers A-D

Using the same sequence of reactions as described for Example 567, butstarting with2-(5-(hydroxymethyl)tetrahydrofuran-2-yl)-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethan-1-one,the title compounds were prepared.

LCMS: Example Name and structure [M + H]⁺ Example 568 Isomer A^(#)

536.30 5-((((2S,5S)-5-(2-Oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)tetrahydrofuran-2-yl)methyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one Example 568 Isomer B^(#)

536.30 5-((((2R,5R)-5-(2-Oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)tetrahydrofuran-2-yl)methyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one Example 568 Isomer C^(#)

536.30 5-((((2S,5R)-5-(2-Oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)tetrahydrofuran-2-yl)methyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one Example 568 Isomer D^(#)

536.30 5-((((2R,5S)-5-(2-Oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)tetrahydrofuran-2-yl)methyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one ^(#)The absolute stereochemistry ofthe isomers of Example 568 were arbitrarily assigned after isolation ofeach diastereoisomer by chiral HPLC.

Example 569:6-(4-[3-[(2R)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]butanoyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1:6-(4-[3-[(2R)-2-Hydroxypropoxy]butanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-[4-[(2E)-but-2-enoyl]piperazin-1-yl]pyridine-3-carbonitrile (2.5 g,9.75 mmol, 1.00 equiv), Cs₂CO₃ (6.49 g, 19.92 mmol, 2.00 equiv),(2R)-propane-1,2-diol (3.7 g, 48.62 mmol, 5.00 equiv) in ACN (30 mL) wasstirred for 24 h at 75° C. After concentration, the residue was purifiedby C18 reverse phase chromatography eluting with H₂O/ACN to afford 1.3 g(40%) of the title compound as a brown oil. LCMS: [M+H]⁺ 333.00.

Step 2:6-(4-[3-[(2R)-2-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]propoxy]butanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-(4-[3-[(2R)-2-hydroxypropoxy]butanoyl]piperazin-1-yl)pyridine-3-carbonitrile(350 mg, 1.05 mmol, 1 equiv), Int-A6 (1.0 g, 3.16 mmol, 3 equiv), andCs₂CO₃ (686.1 mg, 2.11 mmol, 2 equiv) in CAN (15 mL) was stirred for 6 hat 70° C. The resulting mixture was concentrated and the residue wasapplied onto a silica gel column with EtOAc/petroleum ether (1:1) toafford 70 mg (11%) of the title compound as a brown oil. LCMS: [M+H]⁺625.00.

Step 6:6-(4-[3-[(2R)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]butanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-(4-[3-[(2R)-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]propoxy]butanoyl]piperazin-1-yl)pyridine-3-carbonitrile(200 mg, 0.32 mmol, 1 equiv) and TFA (2 ml) in DCM (10 mL) was stirredfor 0.5 h at RT. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/ACN. The residue wasfurther purified by Prep-HPLC yielding the title compound (18.6 mg, 12%)as a white solid. LCMS: [M+H]⁺ 495.10, ¹H NMR (300 MHz, Methanol-d₄) δ8.43 (s, 1H), 8.23 (d, J=6.8 Hz, 1H), 7.77 (dd, J=9.1, 2.2 Hz, 1H), 6.85(dd, J=9.1, 2.6 Hz, 1H), 5.11-5.01 (m, 1H), 4.08-3.89 (m, 1H), 3.89-3.47(m, 10H), 2.83-2.53 (m, 1H), 2.52-2.30 (m, 1H), 1.36 (dd, J=6.3, 1.4 Hz,3H), 1.33-1.07 (m, 3H).

Example 570 Isomer A

(S)-5-(1-Methoxy-3-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yloxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

Example 570 Isomer B

(R)-5-(1-Methoxy-3-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yloxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

Step 1:3-(2-Hydroxy-3-methoxypropoxy)-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propan-1-one

A solution of Int-A21 (1.4 g, 4.89 mmol, 1.00 equiv),3-methoxypropane-1,2-diol (2.6 g, 24.50 mmol, 5.00 equiv), and Cs₂CO₃(3.18 g, 9.76 mmol, 2.00 equiv) in ACN (30 mL) was stirred for 5 h at80° C. After concentration, the residue was purified by C18 reversephase chromatography eluting with H₂O/ACN to afford 1.45 g (76%) of thetitle compound as a white solid. LCMS: [M+H]⁺ 393.17.

Step 2:5-(1-Methoxy-3-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yloxy)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one

A solution of3-(2-hydroxy-3-methoxypropoxy)-1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propan-1-one(1.3 g, 3.31 mmol, 1 equiv), Cs₂CO₃ (2.2 g, 6.75 mmol, 2.04 equiv), andInt-A6 (6.5 g, 19.78 mmol, 5.97 equiv) in ACN (20 mL) was stirred for1.3 h at 80° C. The solids were filtered and the resulting solution wasextracted with EtOAc (3×30 mL) and the organic layers combined. Thesolution was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column eluting withEtOAc/hexane (1:1) to afford 1.3 g (57%) of the title compound as ayellow oil. LCMS: [M+H]⁺ 685.25.

Step 3:(S)-5-(1-Methoxy-3-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yloxy)-4-(trifluoromethyl)pyridazin-3(2H)-one and(R)-5-(1-methoxy-3-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yloxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of5-[[1-methoxy-3-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]oxy]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1.3 g, 1.90 mmol, 1 equiv) and TFA (4 mL, 49.37 mmol, 26.00 equiv) inDMF (20 mL) was stirred for 1 h at RT. After concentration, the residuewas purified by C18 reverse phase chromatography eluting with H₂O/ACN.The residue was further purified by Prep-HPLC and Chiral-Prep-HPLC(CHIRALPAK ID-3, 3 μm, 0.46×5 cm column, eluting with a gradient of MtBE(10 mM NH₃):EtOH=90:10, at a flow rate of 1 mL/min) yielding the titlecompounds as white solids. The absolute stereochemistry was assignedbased on a protein X-ray crystal structure obtained of Example 513A,which confirmed (S)-absolute stereochemistry of the more potentenantiomer.

Example 570 Isomer A

LCMS: [M+H]⁺ 555.30, ¹H NMR (300 MHz, Methanol-d₄) δ 8.61 (s, 2H), 8.25(s, 1H), 5.13-5.11 (m, 1H), 3.96-3.91 (m, 4H), 3.90-3.61 (m, 10H), 3.37(s, 3H), 2.69 (t, J=6.0 Hz, 2H). tR=1.439 min.

Example 570 Isomer B

LCMS: [M+H]⁺ 555.30.

Example 571 Isomer A:6-[4-[(3R)-3-[(2R)-3-Methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrileand Example 571 Isomer B:6-[4-[(3S)-3-[(2S)-3-Methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrileand Example 571 Isomer C:6-[4-[(3R)-3-[(2R)-3-Methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrileand Example 571 Isomer D:6-[4-[(3R)-3-[(2S)-3-Methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1:6-[4-[3-(2-Hydroxy-3-methoxypropoxy)butanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-[(2E)-but-2-enoyl]piperazin-1-yl]pyridine-3-carbonitrile (1.5 g,5.85 mmol, 1.00 equiv), 3-methoxypropane-1,2-diol (3.1 g, 29.21 mmol,5.00 equiv) and Cs₂CO₃ (3.8 g, 11.66 mmol, 2.00 equiv) in ACN (20 mL)was stirred for 2 days at 70° C. The solids were filtered and theresulting solution was concentrated under vacuum. The residue waspurified by C18 reverse phase chromatography eluting with H₂O/ACN toafford 668 mg (31%) of the title compound as a light brown oil. LCMS:[M+H]⁺ 363.20.

Step 2:6-[4-[3-(3-Methoxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]propoxy)butanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-[3-(2-hydroxy-3-methoxypropoxy)butanoyl]piperazin-1-yl]pyridine-3-carbonitrile(630 mg, 1.74 mmol, 1.00 equiv), Int-A6 (3.4 g, 10.34 mmol, 6.00 equiv)and Cs₂CO₃ (1.69 g, 5.19 mmol, 3.00 equiv) in ACN (25 mL) was stirredfor 2 h at 80° C. The solids were filtered and the resulting solutionwas concentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (85:15) to afford 170 mg (15%)of the title compound as a light brown oil. LCMS: [M+H]⁺ 655.28.

Step 3:6-[4-[(3R)-3-[(2R)-3-Methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(3R)-3-[(2S)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(3S)-3-[(2R)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(3S)-3-[(2S)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-[4-[3-(3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]propoxy)butanoyl]piperazin-1-yl]pyridine-3-carbonitrile(110 mg, 0.17 mmol, 1.00 equiv) and TFA (1.25 mL) in DCM (5 mL) wasstirred for 1 h at RT, and then the resulting solution was concentratedunder vacuum. The residue was dissolved in NH₃ (gas)/MeOH (2 mL, 7 M)and stirred for 30 min at RT, and then the resulting solution wasconcentrated under vacuum. The residue was purified by C18 reverse phasechromatography eluting with H₂O/ACN. The residue was further purified byPrep-HPLC and Chiral-Prep-HPLC (Repaired IA, 5 μm, 0.46×10 cm column,eluting with a gradient of MtBE (10 mmol NH₃):MeOH=90:10, at a flow rateof 1 mL/min) yielding the title compounds as white solids. The absolutestereochemistry was arbitrarily assigned for the title compounds.

Example 571 Isomer A

2.1 mg, 4%, LCMS: [M+H]⁺ 525.30, ¹H NMR (300 MHz, Methanol-d₄) δ 8.43(s, 1H), 8.24 (s, 1H), 7.79 (dd, J=9.0, 2.4 Hz, 1H), 6.87 (d, J=9.0 Hz,1H), 5.12-5.03 (m, 1H), 4.03-3.93 (m, 1H), 3.87-3.55 (m, 12H), 3.36 (s,3H), 2.76 (dd, J=15.3, 7.8 Hz, 1H), 2.45 (dd, J=15.3 Hz, 4.2 Hz, 1H),1.26 (d, J=6.3 Hz, 3H). tR=4.653 min

Example 571 Isomer B

1.6 mg, 3%, LCMS: [M+H]⁺ 525.30, ¹H NMR (300 MHz, Methanol-d₄) δ 8.43(s, 1H), 8.24 (s, 1H), 7.79 (dd, J=9.0, 2.4 Hz, 1H), 6.87 (d, J=9.0 Hz,1H), 5.09-5.07 (m, 1H), 4.00-3.96 (m, 1H), 3.87-3.55 (m, 12H), 3.36 (s,3H), 2.76 (dd, J=15.3, 5.1 Hz, 1H), 2.45 (dd, J=15.3, 4.5 Hz, 1H), 1.26(d, J=6.3 Hz, 3H). tR=5.481 min

Example 571 Isomer C

6.0 mg, 12%, LCMS: [M+H]⁺ 525.30, ¹H NMR (300 MHz, Methanol-d₄) δ 8.44(s, 1H), 8.23 (s, 1H), 7.79 (dd, J=9.0, 2.4 Hz, 1H), 6.88 (d, J=8.7 Hz,1H), 5.14-5.07 (m, 1H), 4.04-3.97 (m, 1H), 3.78-3.60 (m, 12H), 3.37 (s,3H), 2.77 (dd, J=15.3, 8.4 Hz, 1H), 2.46 (dd, J=15.3, 4.2 Hz, 1H), 1.21(d, J=6.3 Hz, 3H). tR=7.604 min

Example 571 Isomer D

5.3 mg, 11%), LCMS: [M+H]⁺ 525.30, ¹H NMR (300 MHz, Methanol-d₄) δ 8.44(s, 1H), 8.23 (s, 1H), 7.79 (dd, J=9.0, 2.4 Hz, 1H), 6.87 (d, J=8.4 Hz,1H), 5.11-5.09 (m, 1H), 4.04-3.97 (m, 1H), 3.81-3.56 (m, 12H), 3.37 (s,3H), 2.77 (dd, J=15.3, 9.1 Hz, 1H), 2.46 (dd, J=15.3, 4.2 Hz, 1H), 1.21(d, J=6.3 Hz, 3H). tR=9.953 min

Example 572 Isomer A:6-[4-(3-[[(1S,2S)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]cyclopentyl]oxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrileand Example 572 Isomer B:6-[4-(3-[[(1R,2R)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]cyclopentyl]oxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 1:5-[(2-Hydroxycyclopentyl)oxy]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of Int-A6 (2.4 g), cyclopentane-1,2-diol (1.5 g, 1 equiv),and Cs₂CO₃ (2.4 g) in ACN (20 mL) was stirred for 6 h at 25° C. Thesolids were filtered and the solution was combined and concentratedunder reduced pressure. The residue was applied onto a silica gel columnwith EtOAc/petroleum ether (1/3) to afford 500 mg (9%) of the titlecompound as a solid. LCMS: [M+H]⁺ 395.18.

Step 2: Methyl3-[(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]cyclopentyl)oxy]propanoate

A solution of5-[(2-hydroxycyclopentyl)oxy]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(500 mg, 1.27 mmol, 1 equiv), methyl prop-2-enoate (2.5 mL), and Cs₂CO₃(300 mg, 0.92 mmol, 0.73 equiv) in ACN (20 mL) was stirred for 6 h at25° C. The solution was combined and concentrated under vacuum. Theresidue was applied onto a silica gel column with EtOAc/petroleum ether(1/2) to afford 200 mg (33%) of the title compound as a yellow solid.LCMS: [M+H]⁺ 481.27.

Step 3: Methyl3-[(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]cyclopentyl)oxy]propanoate

A solution of methyl3-[(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]cyclopentyl)oxy]propanoate(200 mg, 0.42 mmol, 1 equiv) in DCM (5 mL) and TFA (1 mL) was stirredfor 1 h at 25° C. The resulting mixture was concentrated to afford 150mg of the title compound as a colorless oil. LCMS: [M+H]⁺ 351.37.

Step 4:3-[(2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]cyclopentyl)oxy]propanoicAcid

A solution of methyl3-[(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]cyclopentyl)oxy]propanoate(150 mg, 0.43 mmol, 1 equiv) and LiOH.H₂O (60 mg, 1.43 mmol, 3.34 equiv)in MeOH (5 mL) and H₂O (5 mL) was stirred for 4 h at 25° C. Afterconcentration under reduced pressure, the residue was purified by C18reverse phase chromatography eluting with H₂O/ACN to afford 100 mg (69%)of the title compound as a white solid. LCMS: [M+H]⁺ 337.35.

Step 5:6-[4-(3-[[(1S,2S)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]cyclopentyl]oxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrileand6-[4-(3-[[(1R,2R)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]cyclopentyl]oxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of3-[(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]cyclopentyl)oxy]propanoicacid (100 mg, 0.30 mmol, 1 equiv), Int-A4 (60 mg, 0.32 mmol, 1.07equiv), HATU (115 mg, 0.30 mmol, 1.02 equiv), and DIPEA (0.3 mL) in DMF(4 mL) was stirred for 1 h at 25° C. After concentration by reducedpressure, the residue was purified by C18 reverse phase chromatographyeluting with H₂O/ACN. The residue was further purified by Prep-HPLC andChiral-Prep-HPLC (CHIRALPAK IF, 5 μm, 2×25 cm column, eluting with agradient of Hexanes (0.1% DEA):EtOH=50:50, at a flow rate of 1 mL/min)yielding (after arbitrary assignment of stereochemistry) the titlecompounds as white solids.

Example 572 Isomer A

46.7 mg, 29%, LCMS: [M+H]⁺ 507.35, ¹H NMR (400 MHz, DMSO-d₆): δ 13.33(s, 1H), 8.50 (d, J=4.0 Hz, 1H), 8.26 (s, 1H), 7.90-7.86 (dd, J=4.0,12.0 Hz 1H), 6.93 (d, J=5.6 Hz, 1H), 5.14-5.12 (m, 1H), 3.98-3.96 (m,1H), 3.90-3.48 (m, 10H), 2.66-2.60 (m, 2H), 2.16-2.08 (m, 1H), 1.98-1.92(m, 1H), 1.72-1.55 (m, 4H). tR=2.982 min.

Example 572 Isomer B

41.9 mg, 26%, LCMS: [M+H]⁺ 507.35, tR=3.054 min.

Example 573 Isomer A:6-[4-(3-[[(2S)-1-Hydroxy-3-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propan-2-yl]oxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrileand Example 573 Isomer B:6-(4-[3-[(2R)-3-Hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 573 Isomer C:6-(4-[3-[(2S)-3-Hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 573 Isomer D:6-[4-(3-[[(2R)-1-Hydroxy-3-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propan-2-yl]oxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

Step 2: Mixture of6-(4-[3-[3-(benzyloxy)-2-hydroxypropoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrileand6-(4-(3-((1-(benzyloxy)-3-hydroxypropan-2-yl)oxy)propanoyl)piperazin-1-yl)nicotinonitrile

A solution of 6-[4-(prop-2-enoyl)piperazin-1-yl]pyridine-3-carbonitrile(1 g, 4.13 mmol, 1 equiv), 3-(benzyloxy)propane-1,2-diol (1.5 g, 8.23mmol, 1.99 equiv) and Cs₂CO₃ (4.0 g, 12.28 mmol, 2.97 equiv) in ACN (10mL) was stirred for 2 h at 80° C. The solids were filtered and theresulting solution was concentrated under reduced pressure. The residuewas applied onto a silica gel column eluting with EtOAc/petroleum ether(1:4) to afford 687 mg (390) of the mixture of the title compounds as alight yellow oil. LCMS: [M+H]⁺ 425.21.

Step 2. Mixture of6-(4-[3-[3-(benzyloxy)-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrileand6-(4-(3-((1-(benzyloxy)-3-((6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-3,6-dihydropyridazin-4-yl)oxy)propan-2-yl)oxy)propanoyl)piperazin-1-yl)nicotinonitrile

A solution of Int-A6 (482 mg, 1.47 mmol, 1 equiv), 684.5 mg (1.61 mmol,1.1 equiv) and the mixture of6-(4-[3-[3-(benzyloxy)-2-hydroxypropoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrileand6-(4-(3-((1-(benzyloxy)-3-hydroxypropan-2-yl)oxy)propanoyl)piperazin-1-yl)nicotinonitrile,and Cs₂CO₃ (955.3 mg, 2.93 mmol, 2.00 equiv) in ACN (30 mL) was stirredfor 1 h at 60° C. The solids were filtered and the resulting solutionwas concentrated under vacuum, and the residue was applied onto a silicagel column eluting with EtOAc/petroleum ether (1:7) to afford 434 mg(41%) of the title compounds as a yellow oil. LCMS: [M+H]⁺ 717.30 [M+H]⁺

Step 3: Mixture of6-[4-(3-[[(2S)-1-hydroxy-3-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propan-2-yl]oxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile,6-(4-[3-[(2R)-3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile,6-(4-[3-[(2S)-3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrileand6-[4-(3-[[(2R)-1-hydroxy-3-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propan-2-yl]oxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

To a solution of the mixture of6-(4-[3-[3-(benzyloxy)-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrileand6-(4-(3-((1-(benzyloxy)-3-((6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-3,6-dihydropyridazin-4-yl)oxy)propan-2-yl)oxy)propanoyl)piperazin-1-yl)nicotinonitrile(434 mg, 0.61 mmol, 1 equiv) in DCM (4 mL) was added BCl₃ (70.8 mg, 0.61mmol, 1.00 equiv) dropwise at 0° C. and the resulting solution wasstirred for 1 h at 0° C. The resulting mixture was concentrated undervacuum and the residue was purified by C18 reverse phase chromatographyeluting with H₂O/ACN. The residue was further purified by Prep-HPLC andChiral-Prep-HPLC (CHIRALCEL OJ-3, 3 μm, 0.46×50 cm column, eluting witha gradient of EtOH (0.1% DEA), at a flow rate of 1 mL/min) yielding thetitle compounds as white solids. The absolute stereochemistry forIsomers A and B was assigned in analogy to Example 513A, based on thePARP7 potency of the more potent enantiomer and in analogy to theExample 513A X-ray. The stereochemistry of Examples 573 Isomers C and Dwas arbitrarily assigned. (The position of the methyl group wasconfirmed by ¹H-NMR).

Example 573 Isomer A

5.1 mg, 2%, LCMS: [M+H]⁺ 497.10, 1 H NMR (300 MHz, DMSO-d₆) δ13.28 (s,1H), 8.50 (d, J=1.8 Hz, 1H), 8.27 (d, J=3.9 Hz, 1H), 7.90 (dd, J=9.3,2.4 Hz, 1H), 6.94 (d, J=9.0 Hz, 1H), 5.27 (d, J=4.8 Hz, 1H), 4.39-4.35(m, 1H), 3.91 (d, J=4.5 Hz, 1H), 3.69-3.65 (m, 6H), 3.57-3.55 (m, 5H),3.44 (d, J=5.7 Hz, 2H), 2.62 (t, J=6.3 Hz, 2H). tR=2.06 min.

Example 573 Isomer B

20.2 mg, 7%, LCMS: [M+H]⁺ 497.10, ¹H NMR (300 MHz, DMSO-d₆) δ 13.30 (s,1H), 8.51 (d, J=1.8 Hz, 1H), 8.24 (s, 1H), 7.90 (dd, J=9.0, 2.4 Hz, 1H),6.94 (d, J=9.3 Hz, 1H), 4.82 (t, J=5.7 Hz, 1H), 4.50 (dd, J=10.6, 3.6Hz, 2H), 3.81-3.74 (m, 2H), 3.70-3.62 (m, 5H), 3.59-3.47 (m, 6H), 2.58(t, J=6.4 Hz, 2H), tR=1.19 min.

Example 573 Isomer C

28.0 mg, 9%, LCMS: [M+H]⁺ 497.25, ¹H NMR (300 MHz, DMSO-d₆) δ 12.24 (br,1H), 8.50 (d, J=2.3 Hz, 1H), 8.30-8.24 (m, 1H), 7.88 (dd, J=9.0, 2.4 Hz,1H), 6.94 (d, J=9.0 Hz, 1H), 5.26-4.81 (br, 1H), 4.81-4.35 (m, 2H),3.91-3.71 (m, 7H), 3.69-3.55 (m, 5H), 3.49-3.42 (m, 1H), 2.61 (dt,J=11.9, 6.2 Hz, 2H). tR=2.11 min.

Example 573 Isomer D

38.8 mg, 13%, LCMS: [M+H]⁺ 497.25, ¹H NMR (300 MHz, DMSO-d₆) δ 12.26 (s,1H), 8.51 (d, J=2.1, 1H), 8.27 (d, J=4.5 Hz, 1H), 7.90 (dd, J=9.0, 2.4Hz, 1H), 6.94 (d, J=9.0 Hz, 1H), 5.27 (d, J=5.1 Hz, 1H), 4.39-4.31 (m,2H), 3.93 (dt, J=9.9, 4.8 Hz, 1H), 3.71-3.63 (m, 6H), 3.57-3.55 (m, 4H),3.44 (d, J=5.7 Hz, 2H), 2.64 (t, J=6.3 Hz, 2H). tR=2.14 min.

Example 574 Isomer A:5-(((2S,5S)-5-(2-Oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-tetrahydrofuran-2-yl)methoxy)-4-(trifluoromethyl)pyridazin-3(2H)-oneand Example 574 Isomer B:5-(((2R,5R)-5-(2-Oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-tetrahydrofuran-2-yl)methoxy)-4-(trifluoromethyl)pyridazin-3(2H)-oneand Example 574 Isomer C:5-(((2S,5R)-5-(2-Oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-tetrahydrofuran-2-yl)methoxy)-4-(trifluoromethyl)pyridazin-3(2H)-oneand Example 574 Isomer D:5-(((2R,5S)-5-(2-Oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-tetrahydrofuran-2-yl)methoxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

Step 1:2-[5-[(Benzyloxy)methyl]oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethan-1-one

A solution of 2-[5-[(benzyloxy)methyl]oxolan-2-yl]acetic acid (2 g, 7.19mmol, 1 equiv), HATU (3.344 g, 8.8 mmol, 1.22 equiv), DIPEA (5.3 mL, 32mmol, 4.46 equiv), and Int-A2 (2.39 g, 8 mmol) in DMF (20 mL) wasstirred for 1 h at 25° C. The reaction was quenched by the addition of150 mL of water. The resulting mixture was washed with 2×150 mL of DCMand 2×15 mL of saturated sodium chloride aqueous solution. The mixturewas dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was applied onto a silica gel column (80 g) withEtOAc/petroleum ether (9/11) to afford 2.45 g (62.34%) of the titlecompound as a yellow solid. LCMS (ESI, m/z): 465.20 [M+H]⁺

Step 2:2-[5-(Hydroxymethyl)oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethan-1-one

A solution of2-[5-[(benzyloxy)methyl]oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethan-1-one(2.43 g, 5 mmol, 1 equiv, 85%), Pd/C (0.6 g) in CH₃OH (40 mL) wasstirred for 2 days at 50° C. under H₂(g) atmosphere. The solids werefiltered out. The resulting mixture was concentrated to afford 1.73 g(64%) of the title compound as a yellow solid. LCMS (ESI, m/z): 375.36[M+H]⁺

Step 3:5-[[5-(2-Oxo-2-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of2-[5-(hydroxymethyl)oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethan-1-one(800 mg, 2.1 mmol, 1 equiv), Int-A6 (3.444 g, 10.5 mmol, 5 equiv), andCs₂CO₃ (2.086 g, 6.3 mmol, 3 equiv) in ACN (10 mL) was stirred for 5 hat 60° C. The solids were filtered and washed with 15 mL x 2 of EtOAc,the organic layers were combined and concentrated. After concentration,the residue was purified by C18 reverse phase chromatography elutingwith H₂O/ACN (1/1) to afford 0.88 g (69.49%) of5-[[5-(2-oxo-2-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-oneas a white solid. LCMS (ESI, m/z): 667.25 [M+H]⁺

Step 4:5-(((2S,5S)-5-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-tetrahydrofuran-2-yl)methoxy)-4-(trifluoromethyl)pyridazin-3(2H)-one,5-(((2R,5R)-5-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-tetrahydrofuran-2-yl)methoxy)-4-(trifluoromethyl)pyridazin-3(2H)-one,5-(((2S,5R)-5-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-tetrahydrofuran-2-yl)methoxy)-4-(trifluoromethyl)pyridazin-3(2H)-one,and5-(((2R,5S)-5-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-tetrahydrofuran-2-yl)methoxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of5-[[5-(2-oxo-2-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methoxy]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(0.86 g, 1.291 mmol), and TFA (2 mL) in DCM (8 mL) was stirred for 1 hat 25° C. After concentration, the residue was purified by C18 reversephase chromatography eluting with H₂O/ACN. Then the diastereomericmixture was purified by Chiral-Prep-HPLC (CHIRALPAK IA-3, 0.46*5 cm; 3um, MtBE (10mMNH₃):EtOH=80:20, 1.0 mL/min) yielding (after arbitraryassignment of stereochemistry) the title compounds as white solids.

Example 574 Isomer A

17.3 mg, 10%, LCMS: 537.05 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 13.33 (s,1H), 8.72 (s, 2H), 8.27 (s, 1H), 4.48-4.56 (m, 1H), 4.36-4.40 (m, 1H),4.19-4.25 (m, 1H), 4.18-4.11 (m, 1H), 3.83-3.89 (m, 4H), 3.65-3.44 (m,4H), 2.68 (t, J=6.4 Hz, 1H), 2.44 (t, J=6 Hz, 1H), 2.04-2.10 (m, 2H),1.84-1.71 (m, 1H), 1.55-1.63 (m, 1H). tR=1.56 min.

Example 574 Isomer B

19.1 mg, 11%, LCMS (ESI, m/z): 537.05 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆)δ 13.29 (s, 1H), 8.73 (s, 2H), 8.25 (s, 1H), 4.47-4.34 (m, 2H),4.25-4.31 (m, 2H), 3.95-3.68 (m, 3H), 3.65-3.45 (m, 4H), 2.73 (dd,J=15.1, 6.6 Hz, 1H), 2.52-2.43 (m, 1H), 2.18-2.00 (m, 1H), 1.68-1.77 (m,1H), 1.54-1.64 (m, 1H). tR=2.06 min.

Example 574 Isomer C

15.6 mg, 9%, LCMS (ESI, m/z): 537.05 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ13.30 (s, 1H), 8.73 (s, 2H), 8.25 (s, 1H), 4.47-4.34 (m, 2H), 4.25-4.31(m, 2H), 3.94-3.78 (m, 4H), 3.81-3.68 (m, 4H), 2.73 (dd, J=15.1, 6.6 Hz,1H), 2.52-2.43 (m, 1H), 2.16-2.00 (m, 2H), 1.68-1.77 (m, 1H), 1.66-1.54(m, 1H). tR=3.79 min.

Example 574 Isomer D

19.1 mg, 11%, LCMS (ESI, m/z): 537.05 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆)δ 13.33 (s, 1H), 8.72 (s, 2H), 8.27 (s, 1H), 4.38 (dd, J=10.6, 5.2 Hz,1H), 4.17-4.25 (m, 1H), 4.12-4.17 (m, 1H), 3.91-3.67 (m, 4H), 3.66-3.45(m, 4H), 2.66-2.74 (m, 1H), 2.44 (dd, J=15.2, 6.1 Hz, 1H), 2.13-1.92 (m,2H), 1.82-1.73 (m, 1H), 1.55-1.63 (m, 1H). tR=4.41 min.

Example 575 Isomer A:4-Chloro-5-(((2S,5S)-5-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-tetrahydrofuran-2-yl)methoxy)pyridazin-3(2H)-oneand Example 575 Isomer B:4-Chloro-5-(((2R,5R)-5-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-tetrahydrofuran-2-yl)methoxy)pyridazin-3(2H)-oneand Example 575 Isomer C:4-Chloro-5-(((2S,5R)-5-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-tetrahydrofuran-2-yl)methoxy)pyridazin-3(2H)-oneand Example 575 Isomer D:4-Chloro-5-(((2R,5S)-5-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-tetrahydrofuran-2-yl)methoxy)pyridazin-3(2H)-one

Step 1:4-Chloro-5-((5-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-tetrahydrofuran-2-yl)methoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one

A solution of2-[5-(hydroxymethyl)oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethan-1-one(900 mg, 2.40 mmol, 1 equiv), NaH (115.4 mg, 4.81 mmol, 2 equiv), Int-A7(2.1 g, 7.11 mmol, 2.96 equiv) in ACN (15 mL) was stirred for 1 h at 60°C. The solvent was concentrated under vacuum and the residue was appliedonto a silica gel column eluting with EtOAc/hexane ether (2:1) to afford920 mg (60.44%) of the title compound as yellow oil. LCMS (ESI, m/z):633 [M+H]⁺

Step 2:4-chloro-5-(((2S,5S)-5-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-tetrahydrofuran-2-yl)methoxy)pyridazin-3(2H)-one,4-chloro-5-(((2R,5R)-5-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-tetrahydrofuran-2-yl)methoxy)pyridazin-3(2H)-one,4-chloro-5-(((2S,5R)-5-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-tetrahydrofuran-2-yl)methoxy)pyridazin-3(2H)-oneand4-chloro-5-(((2R,5S)-5-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-tetrahydrofuran-2-yl)methoxy)pyridazin-3(2H)-one

A solution of4-chloro-5-[[5-(2-oxo-2-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]ethyl)oxolan-2-yl]methoxy]-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(570 mg, 0.90 mmol, 1 equiv), TFA (4 mL) in DCM (20 mL) was stirred for1 h at RT. After concentration, the residue was purified by C18 reversephase chromatography eluting with H₂O/CH₃CN. Then the residue wasfurther purified by Prep-HPLC and Chiral-Prep-HPLC (CHIRALPAK IA-3,0.46*5 cm; 3 um, (Hex:DCM=3:1)(0.1% DEA):EtOH=50:50, 1.0 mL/min)yielding (after arbitrary assignment of stereochemistry) the titlecompounds as white solids.

Example 575 Isomer A

14.8 mg, 3.27%, LCMS (ESI, m/z): 503.30 [M+H]⁺, ¹HNMR (Methanol-d₄, 300MHz) δ: 8.58 (d, J=0.8 Hz, 2H), 8.18 (s, 1H), 4.55-4.51 (m, 1H),4.39-4.33 (m, 3H), 4.09-3.91 (m, 2H), 3.86-3.74 (m, 4H), 3.61-3.56 (m,2H), 2.82 (dd, J=14.7, 8.0 Hz, 1H), 2.59 (dd, J=14.7, 4.6 Hz, 1H),2.28-2.08 (m, 2H), 2.11-1.92 (m, 1H), 1.90-1.75 (m, 1H). tR=2.199 min.

Example 575 Isomer B

11.4 mg, 2.52%, LCMS (ESI, m/z): 503.10 [M+H]⁺, ¹HNMR (Methanol-d₄, 300MHz) δ: 8.60 (d, J=0.9 Hz, 2H), 8.16 (s, 1H), 4.52-4.28 (m, 4H),4.19-3.91 (m, 2H), 3.96-3.73 (m, 4H), 3.71-3.51 (m, 2H), 2.84 (dd,J=14.4, 7.9 Hz, 1H), 2.59 (dd, J=14.4, 4.5 Hz, 1H), 2.36-2.13 (m, 2H),2.01-1.80 (m, 1H), 1.83-1.68 (m, 1H). tR=4.243 min.

Example 575 Isomer C

31.9 mg, 7.05%, LCMS (ESI, m/z): 503.10 [M+H]⁺, ¹HNMR (Methanol-d₄, 300MHz) δ: 8.58 (d, J=0.8 Hz, 2H), 8.18 (s, 1H), 4.58-4.47 (m, 1H),4.39-4.33 (m, 3H), 4.09-3.91 (m, 2H), 3.86-3.74 (m, 4H), 3.61-3.56 (m,2H), 2.82 (dd, J=14.7, 8.0 Hz, 1H), 2.59 (dd, J=14.7, 4.6 Hz, 1H),2.28-2.05 (m, 2H), 2.10-1.92 (m, 1H), 1.90-1.75 (m, 1H). tR=5.652 min.

Example 575 Isomer D

13.5 mg, 2.98%, LCMS (ESI, m/z): 503.10 [M+H]⁺, ¹HNMR (Methanol-d₄, 300MHz) δ: 8.60 (d, J=0.9 Hz, 2H), 8.16 (s, 1H), 4.52-4.28 (m, 4H),4.19-3.91 (m, 2H), 3.96-3.73 (m, 4H), 3.71-3.51 (m, 2H), 2.84 (dd,J=14.4, 7.9 Hz, 1H), 2.59 (dd, J=14.4, 4.5 Hz, 1H), 2.36-2.13 (m, 2H),2.01-1.80 (m, 1H), 1.83-1.68 (m, 1H). tR=8.327 min.

Example 576 Isomer A:6-[4-[(3R)-3-[(2S)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrileand Example 576 Isomer B:6-[4-[(3S)-3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrile

Step 1: (E)-6-[4-[But-2-enoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of (2E)-but-2-enoyl (E)-but-2-enoate (1.05 g, 6.81 mmol, 1.30equiv), TEA (1.515 g), Int-A4 (1 g, 5.31 mmol, 1.00 equiv) in DCM (20mL) was stirred for 1 h at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with EtOAc/petroleum ether (1/1) to afford 1.28 g (94%) of thetitle compound as a white solid. LCMS (ESI, m/z): 257.33 [M+H]+

Step 2:(S)-6-(4-[3-[2-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of(E)-6-[4-[but-2-enoyl]piperazin-1-yl]pyridine-3-carbonitrile (3 g, 11.70mmol, 1 equiv), Cs₂CO₃ (7.6 g) in (S)-propane-1,2-diol (10 mL) wasstirred for 3 days at 80° C. The solids were filtered out. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford 800 mg (20.56%) of thetitle compound as a yellow solid. LCMS (ESI, m/z): 333.27[M+H]⁺

Step 3:(S)-6-(4-[3-[2-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]propoxy]butanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of(S)-6-(4-[3-[2-hydroxypropoxy]butanoyl]piperazin-1-yl)pyridine-3-carbonitrile(800 mg, 2.41 mmol, 1 equiv), Int-A6 (8 g, 24.33 mmol, 10.11 equiv),Cs₂CO₃ (1.6 g, 4.91 mmol, 2.04 equiv) in ACN (40 mL) was stirred for 5 hat 70° C. The solids were filtered out. The solution was concentratedunder vacuum. The residue was applied onto a silica gel column elutingwith EtOAc/petroleum ether to afford 300 mg (19.95%) of the titlecompound as yellow oil. LCMS (ESI, m/z): 625.34[M+H]⁺

Step 4:6-[4-[(3R)-3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrileand6-[4-[(3S)-3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]butanoyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of(S)-6-(4-[3-[2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]propoxy]butanoyl]piperazin-1-yl)pyridine-3-carbonitrile(300 mg, 0.48 mmol, 1 equiv) in TFA (1 mL) and DCM (5 mL) was stirredfor 1 h at 25° C. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN. Then the residuewas further purified by Prep-HPLC and Chiral-Prep-HPLC (CHIRALPAK IE,2*25 cm, 5 um; Hex(0.1% DEA):EtOH=50:50, 1.0 mL/min) yielding the titlecompounds as white solids.

Example 576 Isomer A

13.8 mg, 5.81%, LCMS (ESI, m/z): 495.15 [M+H]⁺, ¹H NMR (DMSO-d₆, 400MHz) δ 13.19 (s, 1H), 8.50 (d, J=4.0 Hz, 1H), 8.26 (s, 1H), 7.90-7.86(dd, J=2.0, 12.4 Hz, 1H), 6.92 (d, J=12.0 Hz, 1H), 5.11-5.10 (m, 1H),3.89-3.83 (m, 1H), 3.69-3.48 (m, 10H), 2.66-2.64 (m, 1H), 2.35-2.28 (m,1H), 1.25 (d, J=12.4 Hz, 3H), 1.12 (d, J=12.4 Hz, 3H). tR=1.486 min.

Example 576 Isomer B

12.3 mg, 5.18%, LCMS (ESI, m/z): 495.15 [M+H]⁺, tR=2.479 min.

Example 577 Isomer A:4-Chloro-5-[[(2S)-1-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]propan-2-yl]oxy]-2,3-dihydropyridazin-3-oneand Example 577 Isomer B:4-Chloro-5-[(2S)-2-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]propoxy]-2,3-dihydropyridazin-3-one

Step 1:(S)-1-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-(2-hydroxypropoxy)propan-1-oneand(S)-1-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-(1-hydroxypropan-2-yloxy)propan-1-one

A solution of1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]prop-2-en-1-one (1.2 g, 4.75mmol, 1 equiv), (2S)-propane-1,2-diol (1806.8 mg, 23.74 mmol, 5 equiv),Cs₂CO₃ (3094.5 mg, 9.50 mmol, 2 equiv) in CH₃CN (20 mL) was stirred for2 days at 75° C. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN to afford 650 mg(41.63%) of the mixture of the title compounds as brown oil. LCMS (ESI,m/z): 329.00 [M+H]⁺

Step 2: Mixture of(S)-4-chloro-5-(1-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yloxy)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-oneand(S)-4-chloro-5-(2-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one

A solution of(S)-1-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-(2-hydroxypropoxy)propan-1-oneand(S)-1-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-(1-hydroxypropan-2-yloxy)propan-1-onemixture (630 mg, 1.92 mmol, 1 equiv), Int-A7 (1.7 g, 5.76 mmol, 3.01equiv), Cs₂CO₃ (1.2 g, 3.83 mmol, 2 equiv) in ACN (15 mL) was stirredfor 2 days at 80° C. The residue was applied onto a silica gel columneluting with EtOAc/petroleum ether (1:1) to afford 480 mg (42.64%) ofthe title compounds as brown oil. LCMS (ESI, m/z): 588.00 [M+H]⁺

Step 3: Mixture of4-chloro-5-[[(2S)-1-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]propan-2-yl]oxy]-2,3-dihydropyridazin-3-oneand4-chloro-5-[(2S)-2-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]propoxy]-2,3-dihydropyridazin-3-one

A mixture of(S)-4-chloro-5-(1-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yloxy)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-oneand(S)-4-chloro-5-(2-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-onemixture (470 mg, 0.80 mmol, 1 equiv), TFA (2 mL) in DCM (10 ml) wasstirred for 0.5 h at room temperature. After concentration, the residuewas purified by C18 reverse phase chromatography eluting with H₂O/CH₃CN.The residue was further purified by Prep-HPLC yielding the titlecompounds as white solids.

Example 577 Isomer A

54.2 mg, 14.82%, LCMS (ESI, m/z): 457.15 [M+H]⁺, 1HNMR (300 MHz,Methanol-d₄) δ 8.32 (d, J=2.7 Hz, 2H), 8.16 (s, 1H), 5.02 (qd, J=6.5,3.3 Hz, 1H), 3.93-3.69 (m, 6H), 3.74-3.53 (m, 6H), 2.66 (t, J=6.0 Hz,2H), 1.37 (s, 3H).

Example 577 Isomer B

30.1 mg, 8.23%, LCMS (ESI, m/z): 457.15 [M+H]+, ¹HNMR (300 MHz,Methanol-d₄) δ 8.32 (d, J=1.5 Hz, 2H), 8.15 (s, 1H), 4.46-4.22 (m, 2H),4.02-3.86 (m, 2H), 3.91-3.74 (m, 5H), 3.66 (dt, J=7.3, 3.3 Hz, 4H), 2.68(t, J=6.0 Hz, 2H), 1.28 (dd, J=76.8, 6.0 Hz, 3H).

Example 578 Isomer A

(S)-4-Chloro-5-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yloxy)pyridazin-3(2H)-one and

Example 578 Isomer B

(S)-4-Chloro-5-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propoxy)pyridazin-3(2H)-one

Step 1:(S)-3-(2-hydroxypropoxy)-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propan-1-oneand(S)-3-(1-hydroxypropan-2-yloxy)-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propan-1-one

A solution of1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]prop-2-en-1-one(1.2 g, 4.19 mmol, 1 equiv), Cs₂CO₃ (2.7 g, 8.29 mmol, 1.98 equiv),(2S)-propane-1,2-diol (1.6 g, 21.03 mmol, 5.02 equiv) in ACN (20 mL) wasstirred for 9 h at 75° C. After concentration, the residue was purifiedby C18 reverse phase chromatography eluting with H₂O/CH₃CN to afford 1.1g (71.42%) of the mixture of title compounds as a white solid. LCMS(ESI, m/z): 363.16 [M+H]⁺

Step 2: Mixture of(S)-4-chloro-5-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yloxy)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-oneand(S)-4-chloro-5-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one

A solution of the mixture of(S)-3-(2-hydroxypropoxy)-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propan-1-oneand(S)-3-(1-hydroxypropan-2-yloxy)-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propan-1-one(700 mg, 1.93 mmol, 1 equiv), Cs₂CO₃ (1255.7 mg, 3.86 mmol, 2 equiv),Int-A7 (1711.0 mg, 5.80 mmol, 3 equiv) in ACN (15 mL) was stirred for 28h at 80° C. The solids were filtered out, the resulting solution wasextracted with EtOAc (3×60 mL) and the organic layers combined. Thesolution was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column eluting withEtOAc/hexane (2:1) to afford 670 mg (55.84%) of the mixture of titlecompounds as yellow oil. LCMS (ESI, m/z): 621.22 [M+H]⁺

Step 3: Mixture of(S)-4-chloro-5-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yloxy)pyridazin-3(2H)-oneand(S)-4-chloro-5-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propoxy)pyridazin-3(2H)-one

A solution of the mixture of(S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]oxy]-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-oneand(S)-4-chloro-5-(2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one mixture (480 mg, 0.77 mmol, 1 equiv), TFA (2 mL) in DCM (10 mL)was stirred for 1 h at RT. After concentration, the residue was purifiedby C18 reverse phase chromatography eluting with H₂O/CH₃CN. Then theresidue was further purified by Prep-HPLC and Chiral-Prep-HPLC(CHIRALPAK IA-3, 0.46*10 cm; 5 um, MtBE (10mMNH3):EtOH=80:20, 1.0mL/min) yielding the title compounds as white solids.

Example 578 Isomer A

84.6 mg, 22.30%, LCMS (ESI, m/z): 491.20[M+H]⁺, ¹HNMR (Methanol-d₄, 300MHz) δ: 8.60 (d, J=0.9 Hz, 2H), 8.16 (s, 1H), 5.08-5.00 (m, 1H),3.94-3.91 (m, 4H), 3.89-3.82 (m, 2H), 3.80-3.62 (m, 6), 2.67 (t, J=5.9Hz, 2H), 1.38 (d, J=6.3 Hz, 3H). tR=2.125 min.

Example 578 Isomer B

51.5 mg, 13.58%, LCMS (ESI, m/z): 491.05 [M+H]⁺, ¹H NMR (Methanol-d₄,300 MHz) δ: 8.60 (d, J=0.8 Hz, 2H), 8.15 (s, 1H), 4.41-4.29 (m, 2H),3.98-3.80 (m, 7H), 3.70-3.67 (m, 4H), 2.69 (t, J=6.0 Hz, 2H), 1.28 (d,J=6.4 Hz, 3H). tR=3.775 min.

Example 579:2-(4-[3-[(2S)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoyl]piperazin-1-yl)pyrimidine-5-carbonitrile

Step 1: 2-[4-(Prop-2-enoyl)piperazin-1-yl]pyrimidine-5-carbonitrile

A solution of Int-A1 (6.4 g, 33.82 mmol, 1 equiv), prop-2-enoylprop-2-enoate (5.1 g, 40.44 mmol, 1.20 equiv) and TEA (6.8 g, 67.20mmol, 1.99 equiv) in DCM (40 mL) was stirred for 1 h at roomtemperature. The resulting solution was concentrated under vacuum, andthe residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (7:3) to afford 3.6 g (43.75%) of the titlecompound as a white solid. LCMS (ESI, m/z): 244.12 [M+H]⁺.

Step 2:2-(4-[3-[(2S)-2-hydroxypropoxy]propanoyl]piperazin-1-yl)pyrimidine-5-carbonitrile

A solution of2-[4-(prop-2-enoyl)piperazin-1-yl]pyrimidine-5-carbonitrile (1 g, 4.11mmol, 1 equiv), (2S)-propane-1,2-diol (0.3 g, 3.94 mmol, 0.96 equiv) andCs₂CO₃ (2.7 g, 8.29 mmol, 2.02 equiv) in ACN (10 mL) was stirred for 1 hat 80° C. in an oil bath. The solids were filtered and the resultingsolution was concentrated under vacuum, and the residue was applied ontoa silica gel column eluting with EtOAc/petroleum ether (3:2) to afford594 mg (45.25%) of the title compound as yellow oil. LCMS (ESI, m/z):320.16 [M+H]⁺.

Step 3:(S)-2-(4-(3-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)propanoyl)piperazin-1-yl)pyrimidine-5-carbonitrile

A solution of methyl2-(4-[3-[(2S)-2-hydroxypropoxy]propanoyl]piperazin-1-yl)pyrimidine-5-carbonitrile(674 mg, 2.11 mmol, 1 equiv), Int-A6 (1.4 g, 4.22 mmol, 2.00 equiv) andCs₂CO₃ (2.1 g, 6.33 mmol, 3.00 equiv) in ACN (10 mL). The resultingsolution was stirred for 1 h at 60° C. in an oil bath, then the solidswere filtered out and the resulting solution was concentrated undervacuum, then the residue was applied onto a silica gel column elutingwith EtOAc/petroleum ether (3:1) to afford 144 mg (11.15%) of the titlecompound as yellow oil. LCMS (ESI, m/z): 612.25[M+H]⁺.

Step 4:2-(4-[3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoyl]piperazin-1-yl)pyrimidine-5-carbonitrile

A solution of2-(4-[3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]propoxy]propanoyl]piperazin-1-yl)pyrimidine-5-carbonitrile(144 mg, 0.24 mmol, 1 equiv) and TFA (2 mL) in DCM (10 mL) was stirredfor 1 h at room temperature. The mixture was concentrated and theresidue was purified by Prep-HPLC yielding the title compound (27.9 mg,24.62%) as a white solid. LCMS (ESI, m/z): 482.05 [M+H]+, ¹H NMR(CD₃OD-d4, 300 MHz) δ8.63 (s, 2H), 8.23 (s, 1H), 5.18-5.08 (m, 1H),3.95-3.90 (m, 4H), 3.87-3.80 (m, 1H), 3.78-3.70 (m, 1H), 3.69-3.56 (m,6H), 2.66 (t, J=5.9 Hz, 2H), 1.36 (d, J=6.3 Hz, 3H).

Example 580 Isomer A:6-(4-[2-[(2S,5S)-5-([[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]methyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 580 Isomer B:6-(4-[2-[(2R,5R)-5-([[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]methyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 580 Isomer C:6-(4-[2-[(2R,5S)-5-([[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]methyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 580 Isomer D:6-(4-[2-[(2S,5R)-5-([[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]methyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1: 1-(Benzyloxy)hex-5-en-2-ol

To a solution of bromo(prop-2-en-1-yl)magnesium (27.4 mL, 1.50 equiv) inTHF (20 mL) was added 2-[(benzyloxy)methyl]oxirane (3 g, 18.27 mmol,1.00 equiv) dropwise under nitrogen at −40° C., and then the resultingsolution was stirred for 1 h at −40° C. The resulting solution wasquenched by 100 mL of aqueous NH₄Cl and extracted with 3×100 mL ofEtOAc. The organic layers were combined, washed with 1×100 mL of brine,dried over anhydrous sodium sulfate and concentrated under vacuum, andthen the residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1:5) to afford 2.16 g (57%) of the title compoundas a yellow oil. LCMS (ESI, m/z): 207.13 [M+H]⁺.

Step 2: Methyl (2Z)-7-(benzyloxy)-6-hydroxyhept-2-enoate

Under nitrogen, a solution of 1-(benzyloxy)hex-5-en-2-ol (2 g, 9.70mmol, 1.00 equiv), methyl prop-2-enoate (4.17 g, 48.44 mmol, 5.00 equiv)and Grubbs 2nd generation catalyst (82 mg, 0.01 equiv) in DCM (25 mL)was stirred for 4 h at 40° C. The resulting solution was concentratedunder vacuum and the residue was purified by C18 reverse phasechromatography eluting with H₂O/ACN to afford 1.4 g (55%) of the titlecompound as a yellow oil. LCMS (ESI, m/z): 265.14 [M+H]⁺.

Step 3: Methyl 2-[5-[(benzyloxy)methyl]oxolan-2-yl]acetate

A solution of methyl (2Z)-7-(benzyloxy)-6-hydroxyhept-2-enoate (46 g, 1equiv) and NaH (0.7 g, 0.1 equiv) in THF (200 mL) was stirred for 12 hat 25° C. The resulting solution was quenched with 200 mL of water,extracted with 3×200 mL of DCM, and the organic layers were combined andwashed with 1×100 mL of brine, dried over anhydrous sodium sulfate andconcentrated under vacuum to afford 46 g of the title compound as abrown oil. LCMS (ESI, m/z): 265.14 [M+H]+

Step 4: 2-[5-[(Benzyloxy)methyl]oxolan-2-yl]acetic Acid

A solution of methyl 2-[5-[(benzyloxy)methyl]oxolan-2-yl]acetate (46 g,174.03 mmol, 1 equiv) and LiOH.H₂O (14.6 mg, 0.35 mmol, 2 equiv) in THF(200 mL) and H₂O (200 mL) was stirred for 2 h at 25° C. The resultingsolution was washed with 1×200 ml of DCM, the aqueous layers wascombined and the pH value of the aqueous layer was adjusted to 4 withHCl (1 M). The resulting solution was extracted with 1×200 mL EtOH, andthe organic layers was combined and concentrated under vacuum to afford40 g (91.83%) of the title compound as light yellow oil. LCMS (ESI,m/z): 251.12 [M+H]+.

Step 5: Synthesis of6-[4-(2-[5-[(benzyloxy)methyl]oxolan-2-yl]acetyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of 2-[5-[(benzyloxy)methyl]oxolan-2-yl]acetic acid (1 g, 4.00mmol, 1.00 equiv), Int-A4 (752 mg, 4.00 mmol, 1.00 equiv), HATU (1.52 g,4.00 mmol, 1.00 equiv) and DIPEA (1.55 g, 11.99 mmol, 3.00 equiv) in DMF(10 mL) was stirred for 1 h at RT. The resulting solution was dilutedwith 50 mL of EtOAc and washed with 3×40 mL of H₂O. The organic layerswas combined, dried over anhydrous sodium sulfate and concentrated undervacuum, and the residue was applied onto a silica gel column elutingwith EtOAc/petroleum ether (6:4) to afford 1.28 g (76%) of the titlecompound as a brown oil. LCMS (ESI, m/z): 421.22 [M+H]⁺.

Step 6:6-(4-[2-[5-(Hydroxymethyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

To a solution of6-[4-(2-[5-[(benzyloxy)methyl]oxolan-2-yl]acetyl)piperazin-1-yl]pyridine-3-carbonitrile(1.28 g, 3.04 mmol, 1.00 equiv) in DCM (120 mL) was added BCl₃/DCM (9.1mL, 1M) dropwise, and then the resulting solution was stirred for 20 minat 0° C. The solution was quenched by 10 mL of MeOH and concentratedunder vacuum and the residue was purified was purified by C18 reversephase chromatography eluting with H₂O/ACN to afford 600 mg (60%) of thetitle compound as a light yellow solid. LCMS (ESI, m/z): 331.17 [M+H]⁺.

Step 7:6-(4-[2-[5-([[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]methyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-(4-[2-[5-(hydroxymethyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile(160 mg, 1.00 equiv), Int-A6 (480 mg, 3.00 equiv) and Cs₂CO₃ (480 mg,3.00 equiv) in ACN (8 mL) was stirred for 1 h at 80° C. The resultingsolution was diluted with 30 mL of EtOAc, washed with 2×20 ml of H₂O and20 ml of brine. The organic layers were combined, dried over anhydroussodium sulfate and concentrated under vacuum, and then the residue wasapplied onto a silica gel column eluting with EtOAc to afford 120 mg ofthe title compound as a brown solid. LCMS (ESI, m/z): 623.25 [M+H]⁺

Step 8:6-(4-[2-[(2S,5S)-5-([[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]methyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand6-(4-[2-[(2R,5R)-5-([[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]methyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand6-(4-[2-[(2R,5S)-5-([[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]methyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand6-(4-[2-[(2S,5R)-5-([[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]methyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of 6-(4-[2-[5-([[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]methyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile(730 mg, 1.17 mmol, 1 equiv) and TFA (1.25 mL) in DCM (5 mL) was stirredfor 1 h at room temperature. The resulting solution was concentratedunder vacuum, and the residue was dissolved in NH₃(gas)/MeOH (2 mL, 7 M)and stirred for 20 min at room temperature. After concentration, theresidue was purified by C18 reverse phase chromatography eluting withH₂O/ACN. The residue was further purified by Prep-HPLC andChiral-Prep-HPLC (CHIRALAPK ID-3, 0.46*10 cm; 3 um, MtBE (0.2%IPAmine):EtOH=70:30, 1.0 mL/min) yielding (after arbitrary assignment ofstereochemistry) the title compounds as white solids.

Example 580 Isomer A

69 mg, 16.43%, LCMS (ESI, m/z): 493.10 [M+H]⁺, ¹H NMR (Methanol-d₄, 300MHz) δ 8.41 (s, 1H), 8.24 (s, 1H), 7.77 (dd, J=9.0, 2.1 Hz, 1H), 6.85(dd, J=9.0, 0.6 Hz, 1H), 4.57 (dd, J=10.5, 3.0 Hz, 1H), 4.39-4.25 (m,3H), 3.80-3.62 (m, 8H), 2.81 (dd, J=15.0, 7.8 Hz, 1H), 2.61 (dd, J=15.0,4.8 Hz, 1H), 2.17-2.10 (m, 2H), 1.94-1.89 (m, 1H), 1.81-1.66 (m, 1H).tR=2.526 min.

Example 580 Isomer B

45.4 mg, 10.81%, LCMS (ESI, m/z): 493.10 [M+H]⁺, ¹H NMR 8.43 (s, 1H),8.22 (s, 1H), 7.78 (dd, J=9.0, 2.4 Hz, 1H), 6.88 (dd, J=9.0, 0.6 Hz,1H), 4.48-4.37 (m, 4H), 3.81-3.62 (m, 8H), 2.86 (dd, J=14.4, 7.8 Hz,1H), 2.61 (dd, J=14.7, 4.8 Hz, 1H), 2.30-2.19 (m, 2H), 1.94-1.82 (m,1H), 1.81-1.69 (m, 1H). tR=4.043 min.

Example 580 Isomer C

49 mg, 11.67%, LCMS (ESI, m/z): 493.10 [M+H]⁺, ¹H NMR (Methanol-d₄, 300MHz) δ 8.41 (s, 1H), 8.24 (s, 1H), 7.77 (dd, J=9.0, 2.1 Hz, 1H), 6.85(dd, J=9.3, 0.8 Hz, 1H), 4.58 (dd, J=10.8, 3.0 Hz, 1H), 4.43-4.26 (m,3H), 3.80-3.62 (m, 8H), 2.81 (dd, J=15.0, 7.8 Hz, 1H), 2.61 (dd, J=15.0,4.8 Hz, 1H), 2.17-2.08 (m, 2H), 1.98-1.94 (m, 1H), 1.77-1.73 (m, 1H).tR=3.168 min.

Example 580 Isomer D

55.5 mg, 13.21%, (ESI, m/z): 493.10 [M+H]⁺, ¹H NMR (Methanol-d₄, 300MHz) δ 8.43 (s, 1H), 8.22 (s, 1H), 7.79 (dd, J=9.0, 2.4 Hz, 1H), 6.88(d, J=9.3, 0.8 Hz, 1H), 4.48-4.38 (m, 4H), 3.85-3.62 (m, 8H), 2.86 (dd,J=14.7, 7.8 Hz, 1H), 2.61 (dd, J=14.7, 4.8 Hz, 1H), 2.24-2.19 (m, 2H),1.95-1.85 (m, 1H), 1.78-1.69 (m, 1H). tR=4.930 min.

Example 581 Isomer A:6-(4-[2-[(2R,5S)-5-([[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]methyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 581 Isomer B:6-(4-[2-[(2S,5S)-5-([[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]methyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 581 Isomer C:6-(4-[2-[(2R,5R)-5-([[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]methyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 581 Isomer D:6-(4-[2-[(2S,5R)-5-([[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]methyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1:(5-[2-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl)methylmethanesulfonate

A solution of6-(4-[2-[5-(hydroxymethyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile(1.5 g, 4.54 mmol, 1 equiv), TEA (0.9 g, 8.89 mmol, 1.96 equiv), Ms₂O(0.95 g) in DCM (20 mL) was stirred for 5 h at room temperature. Theresulting solution was diluted with 20 mL of water and extracted with3×20 mL DCM. The organic layers were combined and dried over anhydroussodium sulfate and concentrated under vacuum to afford 2.3 g (crude) ofthe title compound as a yellow oil. LCMS (ESI, m/z): 409.15[M+H]⁺

Step 2:6-(4-[2-[5-(Azidomethyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of(5-[2-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl)methylmethanesulfonate (1.85 g, 4.53 mmol, 1 equiv), NaN₃ (442 mg, 6.80 mmol,1.50 equiv) in DMF (20 mL) was stirred for 2 h at 90° C. The reactionwas then quenched by the addition of 20 mL of water. The resultingsolution was extracted with 3×30 mL of EtOAc, and the organic layerswere combined, dried over anhydrous sodium sulfate, and concentratedunder vacuum to afford 1.8 g (crude) of the title compound as a yellowoil. LCMS (ESI, m/z): 356.18 [M+H]⁺

Step 3:6-(4-[2-[5-(Aminomethyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-(4-[2-[5-(azidomethyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile(1.6 g, 4.50 mmol, 1 equiv), triphenylphosphine (1.4 g, 5.34 mmol, 1.19equiv) in THF (20 mL) and H₂O (5 mL) was stirred 3 h at 80° C. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/ACN to afford 1.1 g (74.18%) of thetitle compound as a yellow oil. LCMS (ESI, m/z): 330.19[M+H]⁺

Step 4:6-(4-[2-[5-([[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]methyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-(4-[2-[5-(aminomethyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile(400 mg, 1.21 mmol, 1 equiv), TEA (242.4 mg, 2.40 mmol, 1.97 equiv), andInt-A6 (434 mg, 1.32 mmol, 1.09 equiv) in EtOH (20 mL) was stirred for 2h at 80° C. The solvent was concentrated under vacuum and the residuewas applied onto a silica gel column eluting with EtOAc/petroleum ether(1/1) to afford 800 mg of the title compound as a yellow solid. LCMS(ESI, m/z): 622.27[M+H]⁺

Step 5:6-(4-[2-[(2R,5S)-5-([[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]methyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile,6-(4-[2-[(2S,5S)-5-([[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]methyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile,6-(4-[2-[(2R,5R)-5-([[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]methyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand6-(4-[2-[(2S,5R)-5-([[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]methyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-(4-[2-[5-([[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]methyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile(800 mg, 1.29 mmol, 1 equiv), TFA (1 mL) in DCM (10 mL) was stirred for2 h at room temperature. After concentration, the residue was purifiedby C18 reverse phase chromatography eluting with H₂O/CH₃CN. Then theresidue was further purified by Prep-HPLC and Chiral-Prep-HPLC (RepairedIC, 0.46*10 cm; 3 um, (Hex:DCM=1:1)(0.1% DEA):EtOH=50:50, 1.0 mL/min)yielding (after arbitrary assignment of stereochemistry) the titlecompounds as white solids.

Example 581 Isomer A

27.4 mg, 4.33%, LCMS (ESI, m/z): 491.47 [M+H]⁺, ¹H NMR (300 MHz,DMSO-d6) δ: 12.35 (s, 1H), 8.48 (d, J=2.3 Hz, 1H), 7.91-7.80 (m, 2H),6.92-6.89 (m, 2H), 4.24 (q, J=6.4 Hz, 1H), 4.08 (t, J=5.9 Hz, 1H),3.69-3.32 (m, 10H), 2.87-2.65 (m, 1H), 2.51-2.42 (m, 1H), 2.02 (m, 2H),1.69-1.45 (m, 2H). tR=3.364 min.

Example 581 Isomer B

24.7 mg, 3.91%, LCMS (ESI, m/z): 491.47 [M+H]⁺, ¹H NMR (300 MHz,DMSO-d6) δ: 12.35 (s, 1H), 8.49 (d, J=2.3 Hz, 1H), 7.94-7.81 (m, 2H),6.90 (d, J=9.1 Hz, 2H), 4.17 (q, J=6.4 Hz, 1H), 4.02-3.92 (m, 1H),3.69-3.36 (m, 10H), 2.59 (dd, J=15.4, 6.6 Hz, 1H), 2.38 (dd, J=15.4, 6.2Hz, 1H), 2.00-1.80 (m, 2H), 1.66 (dt, J=12.3, 5.5 Hz, 1H), 1.50 (s, 1H).tR=4.177 min.

Example 581 Isomer C

33.6 mg, 5.31%, LCMS (ESI, m/z): 491.47 [M+H]⁺, ¹H NMR (300 MHz,DMSO-d6) δ: 12.42 (s, 1H), 8.52 (d, J=2.4 Hz, 1H), 7.97-7.85 (m, 2H),6.93 (d, J=9.1 Hz, 2H), 4.19 (t, J=6.4 Hz, 1H), 4.00 (s, 1H), 3.67-3.34(m, 10H), 2.62 (dd, J=15.5, 6.5 Hz, 1H), 2.41 (dd, J=15.3, 6.1 Hz, 1H),2.01-1.90 (m, 2H), 1.71 (s, 1H), 1.53 (s, 1H). tR=7.477 min.

Example 581 Isomer D

39.6 mg, 6.26%, LCMS (ESI, m/z): 491.47 [M+H]⁺, ¹H NMR (300 MHz,DMSO-d6) δ: 12.39 (s, 1H), 8.51 (d, J=2.2 Hz, 1H), 7.95-7.83 (m, 2H),6.93 (t, J=8.0 Hz, 2H), 4.26 (t, J=6.3 Hz, 1H), 4.16-4.07 (m, 1H),3.67-3.34 (m, 10H), 2.69 (dd, J=15.1, 6.5 Hz, 1H), 2.45 (dd, J=15.0, 6.3Hz, 1H), 2.11-2.00 (m, 2H), 1.65-1.54 (m, 2H). tR=10.970 min.

Example 582 Isomer A:6-(4-[2-[(2S,5S)-5-[[(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy]methyl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 582 Isomer B:6-(4-[2-[(2R,5R)-5-[[(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy]methyl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 582 Isomer C:6-(4-[2-[(2R,5S)-5-[[(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy]methyl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 582 Isomer D:6-(4-[2-[(2S,5R)-5-[[(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy]methyl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1:6-[4-[2-(5-[[(5-chloro-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]methyl]oxolan-2-yl)acetyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of Int-A7 (1.3 g, 4.5 mmol, 3 equiv),6-(4-[2-[5-(hydroxymethyl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile(500 mg, 1.5 mmol, 1 equiv), NaH (121 mg, 3.0 mmol, 2 equiv, 60%) in ACN(10 mL) was stirred for 1 h at 40° C. The resulting mixture wasconcentrated and the residue was applied onto a silica gel columneluting with EtOAc/petroleum ether (1:1) to afford 420 mg (47.10%) ofthe title compound as yellow oil. LCMS (ESI, m/z): 589.24 [M+H]⁺

Step 2:6-(4-[2-[(2S,5S)-5-[[(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy]methyl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile,6-(4-[2-[(2R,5R)-5-[[(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy]methyl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile,6-(4-[2-[(2R,5S)-5-[[(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy]methyl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand6-(4-[2-[(2S,5R)-5-[[(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy]methyl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-[4-[2-(5-[[(5-chloro-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]methyl]oxolan-2-yl)acetyl]piperazin-1-yl]pyridine-3-carbonitrile(410 mg, 0.70 mmol, 1 equiv), and TFA (2 mL) in DCM (10 mL) was stirredfor 0.5 h at RT. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/ACN. Then the residue wasfurther purified by Prep-HPLC and Chiral-HPLC yielding (after arbitraryassignment of stereochemistry) the title compounds as white solids.

Example 582 Isomer A

12.6 mg, 3.95%, LCMS (ESI, m/z): 459.30 [M+H]+, ¹H NMR (300 MHz,Methanol-d4) δ 8.40 (d, J=0.8 Hz, 1H), 8.17 (s, 1H), 7.75 (dd, J=9.1,2.4 Hz, 1H), 6.82 (dd, J=9.1, 0.9 Hz, 1H), 4.57-4.47 (m, 1H), 4.44-4.27(m, 3H), 3.86-3.59 (m, 8H), 2.80 (dd, J=14.8, 7.8 Hz, 1H), 2.59 (dd,J=14.7, 4.7 Hz, 1H), 2.17-2.07 (m, 2H), 2.02-1.92 (m, 1H), 1.90-1.75 (m,1H). tR=3.894 min.

Example 582 Isomer B

3.0 mg, 4.07%, LCMS (ESI, m/z): 459.30 [M+H]+, ¹H NMR (300 MHz,Methanol-d₄) δ 8.40 (s, 1H), 8.17 (s, 1H), 7.75 (dd, J=9.1, 2.4 Hz, 1H),6.82 (d, J=9.1 Hz, 1H), 4.57-4.47 (m, 1H), 4.44-4.27 (m, 3H), 3.86-3.59(m, 8H), 2.80 (dd, J=14.8, 7.8 Hz, 1H), 2.59 (dd, J=14.8, 4.7 Hz, 1H),2.20-2.09 (m, 2H), 2.08-2.03 (m, 1H), 1.90-1.75 (m, 1H). tR=4.613 min.

Example 582 Isomer C

24.4 mg, 7.64%, LCMS (ESI, m/z): 459.30 [M+H]+, ¹H NMR (300 MHz,Methanol-d₄) δ 8.43 (s, 1H), 8.15 (s, 1H), 7.77 (dd, J=9.1, 2.4 Hz, 1H),6.86 (d, J=9.1 Hz, 1H), 4.50-4.28 (m, 4H), 3.94-3.55 (m, 8H), 2.83 (dd,J=14.4, 7.9 Hz, 1H), 2.58 (dd, J=14.4, 4.6 Hz, 1H), 2.35-2.13 (m, 2H),2.01-1.92 (m, 1H), 1.90-1.75 (m, 1H). tR=8.158 min.

Example 582 Isomer D

18.5 mg, 5.79%, LCMS (ESI, m/z): 459.30 [M+H]+, ¹H NMR (300 MHz,Methanol-d4) δ 8.43 (s, 1H), 8.16 (s, 1H), 7.77 (dd, J=9.1, 2.4 Hz, 1H),6.82 (dd, J=9.1, 0.9 Hz, 1H), 4.45-4.28 (m, 4H), 3.94-3.55 (m, 8H), 2.83(dd, J=14.4, 7.9 Hz, 1H), 2.58 (dd, J=14.4, 4.6 Hz, 1H), 2.27-2.13 (m,2H), 2.01-1.76 (m, 2H). tR=5.253 min.

Example 583 Isomer A:6-(4-[2-[(2S,6S)-6-([[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]methyl)oxan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 583 Isomer B:6-(4-[2-[(2R,6R)-6-([[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]methyl)oxan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1: 1-(Benzyloxy)hept-6-en-2-ol

To a solution of CuI (234 mg, 1.23 mmol, 0.10 equiv) in THF (40 mL) wasadded bromo(but-3-en-1-yl)magnesium (18.3 mL, 114.68 mmol, 1.5 equiv) at−40° C., and the resulting solution was stirred for 10 min at −40° C.2-[(benzyloxy)methyl]oxirane (2 g, 12.18 mmol, 1 equiv) was dropped inand then the resulting solution was stirred for another 1.5 h at thistemperature. The reaction was quenched by the addition of 50 mL ofNH₄Cl, extracted with 3×50 ml of EtOAc, washed with 1×50 ml of brine,dried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1:5) to afford 1.17 g (43.60%) of the titlecompound as a yellow oil. LCMS (ESI, m/z): 221.10 [M+H]⁺

Step 2: Methyl (2Z)-8-(benzyloxy)-7-hydroxyoct-2-enoate

A solution of 1-(benzyloxy)hept-6-en-2-ol (1.6 g, 7.26 mmol, 1 equiv),methyl prop-2-enoate (3.12 g, 0.04 mmol) and Grubbs 2nd generationcatalyst (61.7 mg, 0.07 mmol, 0.01 equiv) in DCM (32 mL) was stirred for12 h at 50° C. in an oil bath. The resulting mixture was concentratedunder vacuum and the residue was applied onto a silica gel columneluting with EtOAc/petroleum ether (1:3) to afford 1.57 g (77.67%) ofthe title compound as light brown oil. LCMS (ESI, m/z): 279.05 [M+H]⁺

Step 3: Methyl 2-[6-[(benzyloxy)methyl]oxan-2-yl]acetate

To a solution of methyl (2Z)-8-(benzyloxy)-7-hydroxyoct-2-enoate (1.4 g,5.03 mmol, 1 equiv) in THF (10 mL) was added NaH (241 mg, 10.04 mmol,2.00 equiv) in several batches. The resulting solution was stirred for 6h at room temperature. The reaction was then quenched by the addition of20 mL of water, extracted with 3×30 ml of EtOAc, washed with 20 ml ofbrine, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1:3) to afford 560 mg (40.0%) of the titlecompound as yellow oil. LCMS (ESI, m/z): 279.05 [M+H]⁺

Step 4: 2-[6-[(benzyloxy)methyl]oxan-2-yl]acetic Acid

A solution of methyl 2-[6-[(benzyloxy)methyl]oxan-2-yl]acetate (510 mg,1.83 mmol, 1 equiv) and NaOH (220 mg, 5.50 mmol, 3.00 equiv) in H₂O (2mL) in THF (10 mL) was stirred for 4 h at room temperature. 1 M HCl wasadded to adjust the pH to 4, and the solution was extracted with 3×5 mlof ethyl acetate. The organic portion was dried over anhydrous sodiumsulfate and concentrated under vacuum. This resulted in 410 mg (84.66%)of the title compound as a yellow solid. LCMS (ESI, m/z): 265.10 [M+H]⁺

Step 5:6-[4-(2-[6-[(benzyloxy)methyl]oxan-2-yl]acetyl)piperazin-1-yl]pyridine-3-carbonitrile

A solution of 2-[6-[(benzyloxy)methyl]oxan-2-yl]acetic acid (400 mg,1.51 mmol, 1 equiv), HATU (575 mg, 1.51 mmol, 1.00 equiv), DIPEA (587mg, 4.54 mmol, 3.00 equiv) and Int-A4 in DMF (5 mL) was stirred for 40min at room temperature. Then resulting solution was diluted with 15 mLof water, extracted with 3×15 mL of EtOAc, washed with 1×15 mL of brine,dried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was applied onto a silica gel column eluting with DCM/MeOH(10:1) to afford 490 mg (71.53%) of the title compound as a light brownsolid. LCMS (ESI, m/z): 435.15 [M+H]⁺

Step 6:6-(4-[2-[6-(Hydroxymethyl)oxan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

To a solution of6-[4-(2-[6-[(benzyloxy)methyl]oxan-2-yl]acetyl)piperazin-1-yl]pyridine-3-carbonitrile(2.1 g, 4.83 mmol, 1 equiv) in DCM (200 mL) at 0° C. was added BCl₃ (7.2mL, 1.5 equiv) dropwise. The resulting solution was stirred for 2 h at0° C. in a water/ice bath. The reaction was quenched by the addition of100 mL of MeOH, and the pH value of the solution was adjusted to 4 withHCl (1 M) and concentrated under vacuum. The residue was purified by C18reverse phase chromatography eluting with H₂O/ACN to afford 680 mg(40.85%) of the title compound as a yellow solid. LCMS (ESI, m/z):345.10 [M+H]⁺

Step 7:6-(4-[2-[6-([[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]methyl)oxan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-(4-[2-[6-(hydroxymethyl)oxan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile(680 mg, 1.97 mmol, 1 equiv), Cs₂CO₃ (1.93 g, 0.01 mmol) and Int-A6(1.94 g, 0.01 mmol) in ACN (20 mL) was stirred for 3 h at 70° C. in anoil bath. The solids were filtered out and the residue was applied ontoa silica gel column eluting with EtOAc/petroleum ether (1:4) to afford860 mg crude product. The crude product was purified by C18 reversephase chromatography eluting with H₂O/ACN to afford 720 mg (57.27%) ofthe title compound as a white solid. LCMS (ESI, m/z): 637.25 [M+H]⁺

Step 8:6-(4-[2-[(2S,6S)-6-([[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]methyl)oxan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand6-(4-[2-[(2R,6R)-6-([[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]methyl)oxan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-(4-[2-[6-([[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]methyl)oxan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile(720 mg, 1.13 mmol, 1 equiv) and TFA (6 mL, 0.05 mmol, 0.05 equiv) inDCM (30 mL) was stirred for 1 h at RT. The resulting mixture wasconcentrated and the crude product was purified by C18 reverse phasechromatography eluting with H₂O/ACN. The crude product was furtherpurified by Prep-HPLC and Chiral-Prep-HPLC (CHIRALCEL OJ-3, 4.6*50 mm, 3um; MeOH (0.1% DEA), 2.0 ml/min) yielding (after arbitrary assignment ofstereochemistry) the title compounds as white solids.

Example 583 Isomer A

80.3 mg, 43.8%, LCMS (ESI, m/z): 507.30 [M+H]⁺, ¹H NMR (CD₃OD-d₄, 300MHz) δ: 8.38 (dd, J=2.4, 0.8 Hz, 1H), 8.17 (d, J=0.9 Hz, 1H), 7.73 (dd,J=9.1, 2.4 Hz, 1H), 6.78 (dd, J=9.1, 0.8 Hz, 1H), 4.46-4.31 (m, 2H),3.90-3.75 (m, 6H), 3.65-3.57 (m, 4H), 2.76 (dd, J=14.5, 8.7 Hz, 1H),2.45 (dd, J=14.4, 3.8 Hz, 1H), 1.96 (d, J=10.8 Hz, 1H), 1.78-1.60 (m,3H), 1.56-1.28 (m, 2H). tR=2.027 min.

Example 583 Isomer B

78.1 mg, 42.6%, LCMS (ESI, m/z): 507.30 [M+H]+, ¹H NMR (CD₃OD-d4, 300MHz) δ 8.38 (dd, J=2.4, 0.8 Hz, 1H), 8.17 (d, J=0.9 Hz, 1H), 7.73 (dd,J=9.1, 2.4 Hz, 1H), 6.78 (dd, J=9.1, 0.8 Hz, 1H), 4.46-4.32 (m, 2H),3.90-3.74 (m, 6H), 3.65-3.56 (m, 4H), 2.76 (dd, J=14.5, 8.7 Hz, 1H),2.45 (dd, J=14.4, 3.8 Hz, 1H), 1.97 (d, J=13.3 Hz, 1H), 1.78-1.60 (m,3H), 1.56-1.28 (m, 2H). tR=2.408 min.

Example 584:5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]oxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1:1-[4-[5-(Trifluoromethyl)pyridin-2-yl]piperazin-1-yl]prop-2-en-1-one

A solution of Int-A18 (1 g, 4.32 mmol, 1 equiv), prop-2-enoylprop-2-enoate (600 mg, 4.76 mmol, 1.10 equiv) and TEA (1.3 g, 12.85mmol, 2.97 equiv) in DCM (50 mL) was stirred for 1 h at roomtemperature. The resulting solution was concentrated under vacuum andthe residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1:1) to afford 750 mg (60.79%) of the titlecompound as a white solid. LCMS (ESI, m/z): 286.11 [M+H]⁺

Step 2:3-[(2S)-2-Hydroxypropoxy]-1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]propan-1-one

A solution of1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]prop-2-en-1-one(750 mg, 1.0 equiv), (2S)-propane-1,2-diol (600 mg, 3.0 equiv) andCs₂CO₃ (2.5 g, 3.0 equiv) in ACN (50 mL) was stirred for 18 h at 80° C.The solid was filtered out and the resulting solution was concentratedunder vacuum. The residue was applied onto a silica gel column elutingwith EtOAc/petroleum ether (2:98), and the residue was further purifiedby C18 reverse phase chromatography eluting with H₂O/ACN to afford 276mg of the title compound as a white solid. LCMS (ESI, m/z): 362.16[M+H]⁺

Step 3:5-[[(2S)-1-(3-Oxo-3-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]oxy]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of3-[(2S)-2-hydroxypropoxy]-1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]propan-1-one(225 mg, 0.62 mmol, 1 equiv), Int-A6 (1.2 g, 3.65 mmol, 5.86 equiv) andCs₂CO₃ (506 mg, 1.55 mmol, 2.49 equiv) in ACN (8 mL) was stirred for 2 hat 80° C. The solid was filtered out and the resulting solution wasconcentrated under vacuum, and the residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (88:12) to afford 70 mg(17.20%) of the title compound as a brown solid. LCMS (ESI, m/z): 654.25[M+H]⁺

Step 4:5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]oxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]oxy]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(125 mg, 0.19 mmol, 1 equiv) and TFA (2 mL) in DCM (5 mL) was stirredfor 2 h at room temperature, then the resulting solution wasconcentrated under vacuum and the residue was purified by Pre-HPLCyielding the title compound (11.8 mg, 11.79%) as a white solid. LCMS(ESI, m/z): 524.10 [M+H]⁺. ¹H NMR (Methanol-d4, 300 MHz) δ 8.38 (dt,J=2.1, 1.0 Hz, 1H), 8.23 (s, 1H), 7.78 (dd, J=9.0, 2.4 Hz, 1H), 6.90 (d,J=9.0 Hz, 1H), 5.18-5.08 (m, 1H), 3.87-3.58 (m, 12H), 2.67 (t, J=6.0 Hz,2H), 1.37 (d, J=6.3 Hz, 3H).

Example 585:5-[[(2S)-1-(3-Oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)butan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1:5-[[(2S)-1-Hydroxybutan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of (2S)-2-aminobutan-1-ol (534 mg, 5.99 mmol, 1 equiv), TEA(1212.4 mg, 11.98 mmol, 2 equiv) and Int-A6 (1969.7 mg, 5.99 mmol, 1.0equiv) in EtOH (20 mL) was stirred for 1 h at 60° C. The solvent wasconcentrated under vacuum and the residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (4/6) to afford 1.1 g (48.13%)of the title compound as yellow oil. LCMS (ESI, m/z): 382.17 [M+H]

Step 2: Methyl3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate

A solution of5-[[(2S)-1-hydroxybutan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1.0 g, 2.62 mmol, 1 equiv), Cs₂CO₃ (2562.3 mg, 7.86 mmol, 3 equiv) andmethyl prop-2-enoate (2256.8 mg, 26.21 mmol, 10 equiv) in ACN (20 mL)was stirred for 6 h at RT. The solid was filtered out and the resultingsolution was concentrated under vacuum. The residue was purified by C18reverse phase chromatography eluting with H₂O/ACN to afford 450 mg(36.71%) of the title compound as a yellow oil. LCMS (ESI, m/z): 468.21[M+H]⁺.

Step 3: Methyl3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate

A solution of methyl3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate(450 mg, 0.96 mmol, 1 equiv) and TFA (0.6 mL) in DCM (3 mL) was stirredfor 1 h at room temperature. The resulting mixture was concentratedunder vacuum to afford 340 mg of the title compound as a yellow oil.LCMS (ESI, m/z): 338.13 [M+H]⁺.

Step 4:3-[(2S)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoicAcid

A solution of methyl3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate(340 mg, 1.01 mmol, 1 equiv) and LiOH (241.4 mg, 10.08 mmol, 10 equiv)in MeOH (10 mL) and H₂O (2 mL) was stirred for 2 h at RT. The resultingsolution was concentrated under vacuum and the residue was purified byC18 reverse phase chromatography eluting with H₂O/ACN to afford 220 mg(67.51%) of the title compound as a yellow oil. LCMS (ESI, m/z): 324.11[M+H]⁺.

Step 5:5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)butan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoicacid (200 mg, 0.62 mmol, 1 equiv), HATU (235.2 mg, 0.62 mmol, 1 equiv),DIPEA (159.9 mg, 1.24 mmol, 2 equiv) and Int-A2 (143.7 mg, 0.62 mmol, 1equiv) in DMF (5 mL) was stirred for 1 h at room temperature and theresulting solution was purified by C18 reverse phase chromatographyeluting with H₂O/ACN. The residue was further purified by Prep-HPLCyielding the title compound (43.2 mg, 13%) as a white solid. LCMS (ESI,m/z): 538.30 [M+H]⁺, ¹H NMR (Methanol-d₄, 300 MHz) δ: 8.61 (d, J=0.9 Hz,2H), 7.96 (s, 1H), 4.01-3.91 (m, 5H), 3.86-3.52 (m, 8H), 2.72 (t, J=6.0Hz, 2H), 1.75-1.55 (m, 2H), 1.01 (t, J=7.5 Hz, 3H).

The following examples in Table E10 were similarly prepared from3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoicacid and the appropriate intermediates as described for Example 585.

TABLE E10 Example Name, structure, analytical data Int. 586

3-[(2S)-2-[[6-oxo-5- (trifluoromethyl)-1,6- dihydropyridazin-4-yl]amino]butoxy] propanoic acid and Int-A55-[[(2S)-1-[3-[4-(5-Chloropyridin-2-yl)piperazin-1-yl]-3-oxopropoxy]butan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one; LCMS[M + H]⁺ 503.25; ¹H NMR (400 MHz, Methanol-d₄) δ 8.07 (d, J = 2.4 Hz,1H), 7.95 (s, 1H), 7.54 (dd, J = 9.2, 2.4 Hz, 1H), 6.81 (d, J = 9.2 Hz,1H), 3.96 (d, J = 8.0 Hz, 1H), 3.84-3.50 (m, 12H), 2.68 (t, J = 6.0 Hz,2H), 1.78-1.52 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 587

3-[(2S)-2-[[6-oxo-5- (trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino]butoxy] propanoic acid and Int-A185-[[(2,S)-1-(3-Oxo-3-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]propoxy)butan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one;LCMS [M + H]⁺ 537.35; ¹H NMR (300 MHz, Methanol-d₄) δ 8.38 (s, 1H), 7.97(s, 1H), 7.77 (dd, J = 9.1, 2.6 Hz, 1H), 6.90 (d, J = 9.1 Hz, 1H),3.97-3.85 (m, 1H), 3.83-3.62 (m, 11H), 3.58-3.52 (m, 1H), 2.70 (t, J =6.0 Hz, 2H), 1.76-1.55 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H). 588

3-[(2S)-2-[[6-oxo-5- (trifluoromethyl)-1,6- dihydropyridazin-4-yl)amino]butoxy] propanoic acid and Int-A35-[[(2S)-1-[3-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]butan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one; LCMS[M + H]⁺ 504.35; ¹H NMR (300 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.45 (s,2H), 7.93 (s, 1H), 6.25-6.20 (m, 1H), 3.98 (d, J = 7.7 Hz, 1H),3.76-3.61 (m, 6H), 3.58-3.49 (m, 6H), 2.60 (t, J = 6.6 Hz, 2H), 1.54(td, J = 7.2, 3.6 Hz, 2H), 0.87 (t, J = 7.4 Hz, 3H).

Example 589:6-(4-[3-[(2S)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]butoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1:6-(4-[3-[(2S)-2-hydroxybutoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of (2S)-butane-1,2-diol (1080 mg, 3 equiv), Cs₂CO₃ (2600 mg,2 equiv) and 6-[4-(prop-2-enoyl)piperazin-1-yl]pyridine-3-carbonitrile(968 mg, 1 equiv) in ACN (10 mL) was stirred for 6 h at 60° C. Thesolids were filtered out and the resulting solution was concentratedunder vacuum, and the residue was purified by C18 reverse phasechromatography eluting with H₂O/ACN to afford 400 mg (30.12%) of thetitle compound as colorless oil. LCMS (ESI, m/z): 333.19 [M+H]⁺

Step 2:6-(4-[3-[(2S)-2-([1-[(4-Methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy)butoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-(4-[3-[(2S)-2-hydroxybutoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile(400 mg, 1.20 mmol, 1 equiv), Cs₂CO₃ (784.2 mg, 2.41 mmol, 2 equiv) andInt-A20 (575.2 mg, 1.81 mmol, 1.5 equiv) in ACN (10 mL, 0.24 mmol, 0.20equiv) was stirred for 6 h at 80° C. The solids were filtered out andthe resulting solution was concentrated under vacuum. The residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether toafford 320 mg (43.27%) of the title compound as a red oil. LCMS (ESI,m/z): 625.27 [M+H]⁺.

Step 3:6-(4-[3-[(2S)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]butoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-(4-[3-[(2S)-2-([1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy)butoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile(300 mg, 0.49 mmol, 1 equiv) and H₂SO₄ (95.7 mg, 0.98 mmol, 2 equiv) inTFA (5 mL, 0.04 mmol, 0.09 equiv) was stirred for 6 h at RT. Theresulting solution was quenched by ice/water (5 mL), and extracted byEtOAc (5 mL), and the organic layer was concentrated under vacuum. Theresidue was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN, and then the residue was further purified by Prep-HPLCyielding the title compound (58.1 mg, 24.07%) as a white solid. LCMS(ESI, m/z): 495.15 [M+H]⁺, ¹H NMR (Methanol-d₄, 300 MHz) δ 8.43 (d,J=1.8 Hz, 1H), 8.24 (s, 1H), 7.79 (dd, J=9.0, 2.4 Hz, 1H), 6.87 (d,J=9.0 Hz, 1H), 5.03-4.96 (m, 1H), 3.89-3.59 (m, 12H), 2.63 (t, J=6.0 Hz,2H), 1.79 (td, J=8.3, 7.8, 5.9 Hz, 2H), 1.04 (t, J=7.4 Hz, 3H).

Example 590:2-(4-(3-(2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yloxy)ethoxy)propanoyl)piperazin-1-yl)pyrimidine-5-carbonitrile

Step 1:2-(4-(3-(2-(6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yloxy)ethoxy)propanoyl)piperazin-1-yl)pyrimidine-5-carbonitrile

A solution of Int-A11 (310 mg, 1.05 mmol, 1.00 equiv), HOBt (212.0 mg,1.57 mmol, 1.5 equiv), EDCI (300.7 mg, 1.57 mmol, 1.5 equiv), Int-A1(197.9 mg, 1.05 mmol, 1 equiv) in DMF (5 mL) was stirred for 4.5 h atRT. After concentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/ACN to afford 22.4 mg (4.58%) of thetitle compound (22.4 mg, 4.58%) as a white solid. LCMS (ESI, m/z):468.15 [M+H]⁺, ¹H NMR (Methanol-d₄, 300 MHz) δ: 8.63 (s, 2H), 8.22 (s,1H), 4.56 (t, J=1.8 Hz, 2H), 3.97-3.91 (m, 4H), 3.86-3.82 (m, 4H),3.70-3.69 (m, 4H), 2.72 (t, J=6.0 Hz, 2H).

Example 591 Isomer A:5-[[(2S)-1-[3-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]butan-2-yl]oxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand Example 591 Isomer B:5-[(2S)-2-[3-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]butoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1:1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-[(2S)-2-hydroxybutoxy]propan-1-oneand(S)-1-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-(1-hydroxybutan-2-yloxy)propan-1-one

A solution of (2S)-butane-1,2-diol (1426.5 mg, 15.83 mmol, 4 equiv),Cs₂CO₃ (2578.7 mg, 7.91 mmol, 2.00 equiv),1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]prop-2-en-1-one (1 g, 3.96mmol, 1 equiv) in ACN (20 mL) was stirred for 5 h at 75° C. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford 820 mg (60.44%) of themixture of the mixture of title compounds as a white solid. LCMS (ESI,m/z): 343.15 [M+H]⁺

Step 2:5-[[(2S)-1-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]butan-2-yl]oxy]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand(S)-5-(2-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)butoxy)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of the mixture1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-[(2S)-2-hydroxybutoxy]propan-1-oneand(S)-1-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-(1-hydroxybutan-2-yloxy)propan-1-one(290 mg, 0.85 mmol, 1 equiv), Cs₂CO₃ (551.2 mg, 1.69 mmol, 2 equiv), andInt-A20 (808.7 mg, 2.54 mmol, 3.00 equiv) in DMF (20 mL) was stirred for6 h at 80° C. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/ACN to afford 400 mg(75.65%) of the mixture of title compounds as a yellow solid. LCMS (ESI,m/z): 625.21 [M+H]⁺

Step 3:5-[[(2S)-1-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]butan-2-yl]oxy]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand5-[(2S)-2-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]butoxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of5-[[(2S)-1-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]butan-2-yl]oxy]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-oneand(S)-5-(2-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)butoxy)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one mixture (336 mg, 0.53 mmol, 1 equiv), and H₂SO₄ (525.0 mg, 5.35mmol, 10 equiv) in TFA (10 mL) was stirred overnight at RT. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN. The residue was further purifiedby Prep-HPLC and Chiral-Prep-HPLC yielding the title compounds as whitesolids.

Example 591 Isomer A

34.7 mg, 32.10%, LCMS (ESI, m/z): 505.25 [M+H]⁺, 1H NMR (300 MHz,Methanol-d₄) δ 8.31 (s, 2H), 8.22 (s, 1H), 4.96-4.92 (m, 1H), 3.84-3.66(m, 7H), 3.64-3.53 (m, 5H), 2.61 (t, J=5.9 Hz, 2H), 1.72 (p, J=6.9 Hz,2H), 1.00 (t, J=7.4 Hz, 3H) and

Example 591 Isomer B

24.4 mg, 22.57%, LCMS (ESI, m/z): 505.25 [M+H]⁺, ¹H NMR (300 MHz,Methanol-d₄) δ 8.31 (s, 2H), 8.21 (s, 1H), 4.47-4.36 (m, 2H), 3.89-3.76(m, 6H), 3.68-3.54 (m, 5H), 2.66 (t, J=6.0 Hz, 2H), 1.64 (p, J=7.3 Hz,2H), 0.98 (t, J=7.5 Hz, 3H).

Example 592:2-(4-[3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]butoxy]propanoyl]piperazin-1-yl)pyrimidine-5-carbonitrile

Step 1:2-(4-[3-[(2S)-2-Hydroxybutoxy]propanoyl]piperazin-1-yl)pyrimidine-5-carbonitrile

A solution of2-[4-(prop-2-enoyl)piperazin-1-yl]pyrimidine-5-carbonitrile (1.5 g, 6.17mmol, 1 equiv), (2S)-butane-1,2-diol (2.8 g, 31.07 mmol, 5.04 equiv) andCs₂CO₃ (4.0 g, 12.28 mmol, 1.99 equiv) in ACN (16 mL) was stirred for 1h at 80° C. in an oil bath. The solids were filtered out and theresulting mixture was concentrated under vacuum, and the residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(3:2) to afford 1.25 g (60.81%) of the title compound as yellow oil.LCMS (ESI, m/z): 334.18 [M+H]⁺.

Step 2:2-(4-[3-[(2S)-2-([1-[(4-Methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy)butoxy]propanoyl]piperazin-1-yl)pyrimidine-5-carbonitrile

A solution of2-(4-[3-[(2S)-2-hydroxybutoxy]propanoyl]piperazin-1-yl)pyrimidine-5-carbonitrile(684 mg, 2.05 mmol, 1 equiv), Int-A20 (980.7 mg, 3.08 mmol, 1.50 equiv)and Cs₂CO₃ (1336.9 mg, 4.10 mmol, 2.00 equiv) in ACN (17.5 mL) wasstirred for 6 h at 80° C. in an oil bath. The solids were filtered out,the resulting solution was concentrated under vacuum, and the residuewas purified by C18 reverse phase chromatography eluting with H₂O/ACN toafford 1.04 g (82.34%) of the title compound as a white solid LCMS (ESI,m/z): 616.25 [M+H]⁺.

Step 3:2-(4-[3-[(2S)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]butoxy]propanoyl]piperazin-1-yl)pyrimidine-5-carbonitrile

A solution of2-(4-[3-[(2S)-2-([1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy)butoxy]propanoyl]piperazin-1-yl)pyrimidine-5-carbonitrile(1.04 g, 1.69 mmol, 1 equiv) and H₂SO₄ (1.7 g, 16.89 mmol, 10 equiv) inTFA (16 mL) was stirred for 1 h at RT. The reluting solution wasconcentrated under vacuum and the residue was purified by Prep-HPLCyielding the title compound (25.2 mg, 3.01%) as a white solid. LCMS(ESI, m/z): 496.10 [M+H]⁺, ¹H NMR (CD₃OD-d₄, 300 MHz,) δ 8.64 (s, 2H),8.24 (d, J=0.9 Hz, 1H), 4.98 (d, J=6.5 Hz, 1H), 3.94-3.88 (m, 4H),3.84-3.68 (m, 8H), 2.63 (t, J=5.9 Hz, 2H), 1.77-1.67 (m, 2H), 1.02 (t,J=7.4 Hz, 3H).

Example 593:5-[[(2S)-1-[3-[4-(5-Chloropyridin-2-yl)piperazin-1-yl]-3-oxopropoxy]-3-methoxypropan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of3-[(2S)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoicacid (180 mg, 0.53 mmol, 1 equiv), HATU (242.1 mg, 0.64 mmol, 1.2equiv), DIPEA (205.7 mg, 1.59 mmol, 3 equiv), and Int-A5 (125.8 mg, 0.64mmol, 1.2 equiv) in DMF (3 mL) was stirred for 1 h at RT. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/ACN yielding the title compound (28.2mg, 10.24%) as a white solid. LCMS (ESI, m/z): 519.25 [M+H]⁺, 1HNMR (300MHz, Methanol-d₄) δ 8.09 (d, J=2.7 Hz, 1H), 7.97 (s, 1H), 7.56 (dd,J=9.1, 2.7 Hz, 1H), 6.85 (d, J=9 Hz, 1H), 4.35-4.13 (m, 1H), 3.94-3.74(m, 2H), 3.76-3.61 (m, 6H), 3.61-3.51 (m, 6H), 3.39 (s, 3H), 2.70 (t,J=6.0 Hz, 2H).

Example 594:5-[[(2S)-1-Methoxy-3-(3-oxo-3-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

5-[[(2S)-1-methoxy-3-(3-oxo-3-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of3-[(2S)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoicacid (180 mg, 0.53 mmol, 1 equiv), HATU (242.1 mg, 0.64 mmol, 1.2equiv), DIPEA (205.7 mg, 1.59 mmol, 3 equiv), Int-A4 (147.2 mg, 0.64mmol, 1.20 equiv) in DMF (3 mL) was stirred for 1 h at room temperature.After concentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/ACN yielding the title compound as awhite solid (45.5 mg, 15.52%). LCMS (ESI, m/z): 553.30 [M+H]⁺ 1H NMR(Methanol-d₄, 300 MHz) δ 7.95 (s, 1H), 7.76 (s, 1H), 7.75 (dd, J=9.1,2.5 Hz, 1H), 6.91 (d, J=9.0 Hz, 1H), 4.22-4.18 (m, 1H), 3.92-3.58 (m,12H), 3.56-3.47 (m, 2H), 3.32 (s, 3H), 2.71 (dd, J=6.0, 6.3 Hz, 2H).

Example 595:6-(4-[3-[(2S)-3-Methyl-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1:5-[[(2S)-1-Hydroxy-3-methylbutan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of Int-A6 (1 g, 3.04 mmol, 1 equiv), TEA (613.8 mg, 6.07mmol, 1.99 equiv), and (2S)-2-amino-3-methylbutan-1-ol (347.7 mg, 3.37mmol, 1.11 equiv) in EtOH (30 mL) was stirred for 15.5 h at RT. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column eluting with EtOAc/petroleum ether (1/4) toafford 600 mg (49.88%) of the title compound as yellow oil. LCMS (ESI,m/z): 396.19 [M+H]⁺

Step 2: Methyl3-[(2S)-3-methyl-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate

A solution of5-[[(2S)-1-hydroxy-3-methylbutan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1.2 g, 3.03 mmol, 1 equiv), Cs₂CO₃ (1.97 g, 2 mmol), and methylprop-2-enoate (395.4 mg, 4.59 mmol, 1.51 equiv) in ACN (20 mL) wasstirred for 2 h at RT. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column withEtOAc/petroleum ether (3/17) to afford 470 mg (32.17%) of the titlecompound as a yellow oil. LCMS (ESI, m/z): 482.22 [M+H]⁺

Step 3: Methyl3-[(2S)-3-methyl-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate

A solution of methyl3-[(2S)-3-methyl-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate(470 mg, 0.98 mmol, 1 equiv), TFA (1 mL) in DCM (10 mL) was stirred 2 hat RT. The resulting mixture was concentrated under vacuum to afford 400mg of the title compound as a yellow crude oil. LCMS (ESI, m/z): 352.14[M+H]⁺

Step 4:3-[(2S)-3-Methyl-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoicAcid

A solution of methyl3-[(2S)-3-methyl-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate(400 mg, 1.14 mmol, 1 equiv), and LiOH.H₂O (143 mg, 3.41 mmol, 2.99equiv) in MeOH (10 mL) was stirred for 6 h at RT. The pH value of thesolution was adjusted to 4 with HCl (1 M). The resulting mixture wasconcentrated under vacuum. After concentration, the residue was purifiedby C18 reverse phase chromatography eluting with H₂O/ACN to afford 130mg (33.85%) of the title compound as a yellow oil. LCMS (ESI, m/z):338.12 [M+H]⁺

Step 5:6-(4-[3-[(2S)-3-Methyl-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of3-[(2S)-3-methyl-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoicacid (100 mg, 0.30 mmol, 1 equiv), HATU (123.9 mg, 0.33 mmol, 1.10equiv), DIPEA (77 mg, 0.60 mmol, 2.01 equiv), Int-A4 (62 mg, 0.33 mmol,1.11 equiv) in DMF (4 mL) was stirred for 1 h at room temperature. Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/ACN. Then the residue was furtherpurified by Prep-HPLC yielding the title compound (106.5 mg, 70.78%) asa white solid. LCMS (ESI, m/z): 508.2 [M+H]⁺, ¹H NMR (300 MHz, DMSO-d6)δ: 12.39 (s, 1H), 8.48 (d, J=2.3 Hz, 1H), 7.93 (s, 1H), 7.85 (dd, J=9.1,2.4 Hz, 1H), 6.89 (d, J=9.1 Hz, 1H), 6.08 (m, 1H), 3.84 (s, 1H),3.65-3.52 (m, 12H), 2.55 (t, J=6.4 Hz, 2H), 1.85 (q, J=6.8 Hz, 1H), 0.87(dd, J=8.8, 6.7 Hz, 6H).

Example 596:6-(4-[3-[(2R,3R)-3-Methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1: (2R,3R)-2-amino-3-methoxybutan-1-ol

A solution of (2S,3R)-2-amino-3-methoxybutanoic acid (1 g, 7.51 mmol, 1equiv), diborane hydrogen (15.0 mL, 1 mol/L, 2 equiv) in THF (15 mL) wasstirred for 12 h at RT. The reaction was quenched by the addition of 15mL of methanol. The resulting mixture was diluted with 15 mL of waterand washed with 2×30 ml of DCM. The organic layers were combined anddried over Na₂SO₄. The resulting mixture was concentrated to afford 2.2g (crude) of the title compound as colorless oil. LCMS (ESI, m/z):120.09 [M+H]⁺

Step 2:5-[[(2R,3R)-1-Hydroxy-3-methoxybutan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of (2R,3R)-2-amino-3-methoxybutan-1-ol (2.18 g, 18.29 mmol, 1equiv), Int-A6 (2.46 g, 7.48 mmol, 0.41 equiv), and TEA (3.7 g, 36.56mmol, 2.00 equiv) in EtOH (10 mL, 1.00 equiv) was stirred for 1 h at 80°C. The resulting mixture was concentrated under vacuum. The residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(3/7) to afford 1.63 g (21.6%) of the title compound as a yellow oil.LCMS (ESI, m/z): 412.18 [M+H]⁺

Step 3: Methyl3-[(2R,3R)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate

A solution of5-[[(2R,3R)-1-hydroxy-3-methoxybutan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1.62 g, 3.94 mmol, 1 equiv), Cs₂CO₃ (2.6 g, 7.87 mmol, 2.00 equiv), andmethyl prop-2-enoate (1.7 g, 19.68 mmol, 5.00 equiv) in ACN (10 mL) wasstirred for 1 h at RT. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (3/7) to afford 870 mg (44.4%) of the titlecompound as yellow oil. LCMS (ESI, m/z): 498.22[M+H]⁺

Step 4: Methyl3-[(2R,3R)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate

A solution of methyl3-[(2R,3R)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate(850 mg, 1.71 mmol, 1 equiv) in DCM (10 mL) and TFA (1 mL) was stirredfor 1 h at RT. The pH value of the solution was adjusted to 8 withethanolamine. The resulting solution was diluted with 20 mL of water andextracted with 4×20 mL of DCM. The organic layers were combined anddried over Na₂SO₄. The resulting solution was concentrated under vacuumto afford 640 mg of the title compound as yellow oil. LCMS (ESI, m/z):368.14 [M+H]⁺

Step 5:3-[(2R,3R)-3-Methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoicAcid

A solution of methyl3-[(2R,3R)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate(620 mg, 1.69 mmol, 1 equiv), and LiOH.H₂O (354.2 mg, 8.44 mmol, 5.00equiv) in MeOH (15 mL) and water (5 mL, 277.54 mmol, 164.43 equiv) wasstirred for 1 h at RT. After concentration, the pH value of the solutionwas adjusted to 5 with HCl (1 M). The resulting solution was extractedwith 5×25 mL of DCM. The organic layers were combined and dried overNa₂SO₄. The resulting solution was concentrated under vacuum to afford500 mg (84%) of the title compound as a yellow solid. LCMS (ESI, m/z):354.12 [M+H]⁺

Step 6:6-(4-[3-[(2R,3R)-3-Methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of3-[(2R,3R)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoicacid (200 mg, 0.57 mmol, 1 equiv), DIPEA (219.5 mg, 1.70 mmol, 3.0equiv), Int-A4 (127.2 mg, 0.57 mmol, 1.00 equiv), and HATU (322.9 mg,0.85 mmol, 1.5 equiv) in DMF (4 mL) was stirred for 1 h at roomtemperature. The resulting solution was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN. The residue was further purifiedby Prep-HPLC yielding the title compound (58.4 mg, 19.7%) as a whitesolid. LCMS (ESI, m/z): 524.51 [M+H]⁺, ¹H NMR (400 MHz, Methanol-d₄) δ:8.44 (dd, J=2.4, 0.8 Hz, 1H), 7.95 (s, 1H), 7.77 (dd, J=9.1, 2.3 Hz,1H), 6.87 (dd, J=9.1, 0.8 Hz, 1H), 3.99 (s, 1H), 3.87-3.54 (m, 13H),3.37 (s, 3H), 2.68 (t, J=5.9 Hz, 2H), 1.20 (d, J=6.2 Hz, 3H).

Example 597:6-(4-[3-[(2S)-2-[(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1:4-Chloro-5-[[(2S)-1-hydroxypropan-2-yl]amino]-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of Int-A7 (3 g, 10.16 mmol, 1 equiv), TEA (3.1 g, 30.48 mmol,3 equiv), and (2S)-2-aminopropan-1-ol (2.3 g, 30.48 mmol, 3 equiv) inEtOH (30 mL) was stirred for 16 h at 80° C. After concentration, theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1:1) to afford 2 g (58.95%) of the title compoundas a yellow oil. LCMS (ESI, m/z): 334.13 [M+H]⁺

Step 2: (S)-Ethyl3-(2-(5-chloro-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-ylamino)propoxy)propanoate

A solution of4-chloro-5-[[(2S)-1-hydroxypropan-2-yl]amino]-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(2 g, 5.99 mmol, 1 equiv), Cs₂CO₃ (3.9 g, 11.98 mmol, 2 equiv), andethyl prop-2-enoate (6.0 g, 59.90 mmol, 10 equiv) in ACN (30 mL) wasstirred for 1 h at RT. The solids were filtered out. The resultingmixture was concentrated under vacuum to afford 2.3 g (88.47%) of thetitle compound as a yellow oil. LCMS (ESI, m/z): 434.18 [M+H]⁺

Step 3: (S)-Ethyl3-(2-(5-chloro-6-oxo-1,6-dihydropyridazin-4-ylamino)propoxy)propanoate

A solution of (S)-ethyl3-(2-(5-chloro-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-ylamino)propoxy)propanoate(5.3 g, 12.21 mmol, 1 equiv), and TFA (6 mL, 80.78 mmol, 6.61 equiv) inDCM (30 mL) was stirred for 1 h at RT. The resulting mixture wasconcentrated under vacuum to afford 3.34 g crude of the title compoundas yellow oil. LCMS (ESI, m/z): 304.10 [M+H]⁺

Step 4:3-[(2S)-2-[(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoicAcid

A solution of (S)-ethyl3-(2-(5-chloro-6-oxo-1,6-dihydropyridazin-4-ylamino)propoxy)propanoate(5.2 g, 17.12 mmol, 1 equiv), LiOH (3.6 g, 85.60 mmol, 5 equiv), H₂O (10mL) in MeOH (30 mL) was stirred for 4 h at room temperature. The pHvalue of the solution was adjusted to 5 with HCl (1 M). Afterconcentration, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford 2.14 g (45.34%) of thetitle compound as yellow oil. LCMS (ESI, m/z): 276.07 [M+H]⁺

Step 5:6-(4-[3-[(2S)-2-[(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of3-[(2S)-2-[(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoicacid (209 mg, 0.76 mmol, 1 equiv), DIEA (285 mg, 2.27 mmol, 3 equiv),HATU (275 mg, 0.76 mmol, 1 equiv), Int-A4 (135 mg, 0.76 mmol, 1 equiv)in DMF (1 mL) was stirred for 2 h at room temperature. 2-aminoethan-1-ol(0.2 mL) was added and stirred for 2 h at room temperature. The residuewas purified by C18 reverse phase chromatography eluting with H₂O/ACNyielding the title compound (121.1 mg 35.45%) as a white solid. LCMS(ESI, m/z): 446.15 [M+H]⁺, ¹H NMR (DMSO-d₆, 300 MHz) δ: 8.51 (d, J=2.3Hz, 1H), 7.90-7.86 (m, 2H), 6.92 (dd, J=9.2, 0.8 Hz, 1H), 6.01 (d, J=9.0Hz, 1H), 4.10-4.01 (m, 1H), 3.72-3.62 (m, 6H), 3.56-3.54 (ddd, J=12.9,7.1, 4.1 Hz, 4H), 3.47-3.39 (m, 2H), 2.63-2.49 (t, J=6.5 Hz, 2H), 1.15(d, J=6.5 Hz, 3H).

Example 598:4-Chloro-5-[[(2S)-1-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]propan-2-yl]amino]-2,3-dihydropyridazin-3-one

A solution of3-[(2S)-2-[(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoicacid (198 mg, 0.72 mmol, 1 equiv), DIEA (491 mg, 3.80 mmol, 5 equiv),HATU (275 mg, 0.72 mmol, 1 equiv) in DMF (0.5 mL) and Int-A3 (199 mg,1.00 mmol, 1 equiv) in DMF (0.5 mL) was stirred for 0.5 h at RT. Theresidue was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN yielding the title compound (171.8 mg 52.32%) as a whitesolid. LCMS (ESI, m/z): 456.05 [M+H]⁺, ¹H NMR (DMSO-d₆, 300 MHz) δ:12.48 (s, 1H), 8.44 (s, 2H), 7.87 (s, 1H), 6.02 (d, J=9.1 Hz, 1H),4.09-4.00 (dt, J=15.3, 6.5 Hz, 1H), 3.70-3.61 (m, 6H), 3.53-3.45 (m,6H), 2.59-2.51 (t, J=6.5 Hz, 2H), 1.16 (d, J=6.5 Hz, 3H).

Example 599:(S)-4-Chloro-5-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-ylamino)pyridazin-3(2H)-one

A solution of3-[(2S)-2-[(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoicacid (200 mg, 0.73 mmol, 1 equiv), HATU (413.8 mg, 1.09 mmol, 1.5equiv), DIEA (281.3 mg, 2.18 mmol, 3 equiv), Int-A2 (202.1 mg, 0.87mmol, 1.2 equiv) in DMF (3 mL) was stirred for 1 h at RT. Afterconcentration, the residue was purified by Prep-HPLC yielding the titlecompound (174.6 mg, 49.13%) as a white solid. LCMS (ESI, m/z): 490.25[M+H]⁺, ¹HNMR (Methanol-d₄, 300 MHz) δ: 8.60 (d, J=0.9 Hz, 2H), 7.92 (s,1H), 4.09 (q, J=7.0, 4.2 Hz, 1H), 3.98-3.87 (m, 4H), 3.85-3.73 (m, 2H),3.70-3.61 (m, 5H), 3.52 (dd, J=9.7, 7.5 Hz, 1H), 2.69 (t, J=5.9 Hz, 2H),1.27 (d, J=6.6 Hz, 3H).

Example 600:6-(4-[3-[(2S)-2-[(5-Bromo-6-oxo-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1:4-Bromo-5-[[(2S)-1-hydroxypropan-2-yl]amino]-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of Int-A8 (6 g, 15.62 mmol, 1 equiv), (2S)-2-aminopropan-1-ol(3519.5 mg, 46.86 mmol, 3.00 equiv) and TEA (4741.5 mg, 46.86 mmol, 3equiv) in EtOH (50 mL) was stirred for 4 h at 80° C. The resultingsolution was concentrated under vacuum, and the residue was applied ontoa silica gel column eluting with EtOAc/petroleum ether (1:1) to afford4.2 g (71.07%) of the title compound as a white solid. LCMS (ESI, m/z):378.08 [M+H]⁺

Step 2: Tert-butyl3-[(2S)-2-[(5-bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoate

A solution of4-bromo-5-[[(2S)-1-hydroxypropan-2-yl]amino]-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(4.1 g, 10.84 mmol, 1 equiv), Cs₂CO₃ (7061.7 mg, 21.67 mmol, 2 equiv)and tert-butyl prop-2-enoate (13889.6 mg, 108.37 mmol, 10 equiv) in ACN(80 mL) was stirred for 1.5 h at 40° C. The solids was filtered out andthe resulting solution was concentrated under vacuum. The residue waspurified by C18 reverse phase chromatography eluting with H₂O/ACN toafford 4.2 g (76.4%) of the title compound as a yellow oil. LCMS (ESI,m/z): 506.17 [M+H]⁺

Step 3:3-[(2S)-2-[(5-Bromo-6-oxo-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoicacid

A solution of tert-butyl3-[(2S)-2-[(5-bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoate(2.7 g, 5.33 mmol, 1 equiv) and TFA (6 mL) in DCM (30 mL) was stirredfor 4 h at room temperature. The resulting solution was concentratedunder vacuum, and the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford 2 g of the titlecompound as a crude yellow solid. LCMS (ESI, m/z): 320.02 [M+H]⁺

Step 4:6-(4-[3-[(2S)-2-[(5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of3-[(2S)-2-[(5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoicacid (200 mg, 0.62 mmol, 1 equiv), HOBT (126.6 mg, 0.94 mmol, 1.5equiv), EDCI (179.6 mg, 0.94 mmol, 1.5 equiv), DIPEA (242.2 mg, 1.87mmol, 3.0 equiv) and Int-A4 (117.6 mg, 0.62 mmol, 1.00 equiv) in DMF (4mL) was stirred for 2 h at room temperature. The resulting solution waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN.After concentration, the residue was further purified by Prep-HPLCyielding the title compound (36.1 mg, 11.78%) as a white solid. LCMS(ESI, m/z): 492.10 [M+H]+, ¹HNMR (DMSO-d₆, 300 MHz) δ 12.50 (s, 1H),8.51 (d, J=1.8 Hz, 1H), 7.90 (dd, J=9.0, 2.4 Hz, 1H), 7.79 (s, 1H), 6.93(d, J=9.0 Hz, 1H), 5.77 (d, J=9.3 Hz, 1H), 4.10-4.01 (m, 1H), 3.73-3.44(m, 12H), 2.60 (t, J=6.4 Hz, 2H), 1.16 (d, J=6.5 Hz, 3H).

Example 601:4-Bromo-5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-2,3-dihydropyridazin-3-one

A solution of3-[(2S)-2-[(5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoicacid (200 mg, 0.62 mmol, 1 equiv), HOBT (126.6 mg, 0.94 mmol, 1.5equiv), EDCI (179.6 mg, 0.94 mmol, 1.5 equiv), DIPEA (242.2 mg, 1.87mmol, 3.0 equiv) and Int-A2 (144.4 mg, 0.62 mmol, 1.00 equiv) in DMF (4mL) was stirred for 2 h at room temperature. The resulting solution waspurified by C18 reverse phase chromatography eluting with H₂O/ACN. Afterconcentration, the residue was further purified by Prep-HPLC yieldingthe title compound (14.9 mg, 4.46%) as a white solid. LCMS (ESI, m/z):536.10 [M+H]+, ¹H NMR (DMSO-d₆, 300 MHz) δ 12.50 (s, 1H), 8.73 (d, J=0.6Hz, 2H), 7.79 (s, 1H), 5.76 (d, J=9.3 Hz, 1H), 4.12-4.01 (m, 1H),3.87-3.47 (m, 12H), 2.60 (t, J=6.5 Hz, 2H), 1.16 (d, J=6.5 Hz, 3H).

Example 602:4-Bromo-5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-2,3-dihydropyridazin-3-one

A solution of3-[(2S)-2-[(5-bromo-6-oxo-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoicacid (200 mg, 0.62 mmol, 1 equiv), HOB\T (126.6 mg, 0.94 mmol, 1.5equiv), EDCI (179.6 mg, 0.94 mmol, 1.5 equiv), DIPEA (242.2 mg, 1.87mmol, 3.0 equiv) and Int-A3 (124.1 mg, 0.62 mmol, 1.00 equiv) in DMF (4mL) was stirred for 2h at room temperature. The resulting solution waspurified by C18 reverse phase chromatography eluting with H₂O/ACN. Afterconcentration, the residue was further purified by Prep-HPLC yieldingthe title compound (15.3 mg, 4.89%) as a white solid. LCMS (ESI, m/z):500.05 [M+H]+, ¹HNMR (DMSO-d₆, 300 MHz) δ 12.48 (s, 1H), 8.45 (s, 2H),7.78 (s, 1H), 5.75 (d, J=9.0 Hz, 1H), 4.10-4.01 (m, 1H), 3.71-3.47 (m,12H), 2.60 (t, J=6.5 Hz, 2H), 1.17 (d, J=6.5 Hz, 3H).

Example 603:5-[[(2S)-1-Hydroxy-3-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: Tert-butyl (4R)-4-(hydroxymethyl)-2,2-dimethyl-,3-oxazolidine-3-carboxylate

A solution of 3-tert-butyl 4-methyl(4S)-2,2-dimethyl-1,3-oxazolidine-3,4-dicarboxylate (10 g, 38.565 mmol,1.00 equiv), NaBH₄ (2.92 g, 77.130 mmol, 2.00 equiv), MeOH (30 mL), andCaCl₂ (12.84 g, 115.695 mmol, 3.00 equiv) in THF (150 mL) was stirredfor 1 h at RT. The reaction was quenched by the addition of 30 mL ofwater, extracted with 3×100 mL of EtOAc, dried over anhydrous sodiumsulfate and concentrated under vacuum to afford 9.38 g of the titlecompound as a yellow oil LCMS (ESI, m/z): 232.15 [M+H]+.

Step 2: Tert-butyl(4R)-4-[(3-methoxy-3-oxopropoxy)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate

A solution of tert-butyl(4R)-4-(hydroxymethyl)-2-methyl-1,3-oxazolidine-3-carboxylate (9.38 g,43.17 mmol, 1.00 equiv), Cs₂CO₃ (28.1 g, 86.24 mmol, 2.00 equiv), andmethyl prop-2-enoate (18.6 g, 216.05 mmol, 5.00 equiv) in ACN (80 mL)was stirred for 3 h at room temperature. The solids were filtered outand the residue was concentrated under vacuum to afford 9.92 g of thetitle compound as a crude yellow oil LCMS (ESI, m/z): 318.18 [M+H]⁺

Step 3: Methyl3-[[(4R)-2,2-dimethyl-1,3-oxazolidin-4-yl]methoxy]propanoate

A solution of tert-butyl(4R)-4-[(3-methoxy-3-oxopropoxy)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(9.92 g, 31.26 mmol, 1.00 equiv) in HCl/dioxane (100 mL) was stirred for1 h at room temperature. The resulting mixture was concentrated toafford 9.6 g of the title compound as a crude yellow oil. LCMS (ESI,m/z): 218.14 [M+H]⁺.

Step 4: Methyl3-[(2S)-3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate

A solution of methyl3-[[(4R)-2,2-dimethyl-1,3-oxazolidin-4-yl]methoxy]propanoate (9.6 g,44.19 mmol, 1.00 equiv), DIPEA (11421.4 mg, 88.37 mmol, 2.00 equiv),Int-A6 (14527.8 mg, 44.19 mmol, 1.00 equiv) in IPA (80 mL) was stirredfor 1 h at 60° C. The resulting mixture was concentrated under vacuumand the residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (2:3) to afford 5.5 g (26.51%) of the titlecompound as a yellow oil. LCMS (ESI, m/z): LCMS (ESI, m/z): 470.10[M+H]⁺.

Step 5: Methyl3-[(2S)-3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate

A solution of methyl3-[(2S)-3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate(5.5 g, 11.71 mmol, 1.00 equiv), and TFA (5 mL) in DCM (25 mL) wasstirred for 40 min at RT. The resulting mixture was concentrated toafford 570 mg (14.34%) of the title compound as a yellow oil. LCMS (ESI,m/z): 340.00 [M+H]⁺.

Step 6: Methyl3-[(2S)-3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoicAcid

A solution of methyl3-[(2S)-3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate(570 mg, 1.68 mmol, 1.00 equiv), LiOH (120.70 mg, 5.04 mmol, 3.00equiv), and H₂O (3 mL) in THF (15 mL) was stirred for 3 h at RT. Themixture was diluted with 5 mL of water, and extracted with 10 mL ofEtOAc. The aqueous layers were combined, the pH was adjusted to 4 withHCl (1M), and concentrated under vacuum to afford 380 mg (69.54%) of thetitle compound as yellow oil. LCMS (ESI, m/z): 326.09 [M+H]+.

Step 7:5-[[(2S)-1-hydroxy-3-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of3-(3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoicacid (100 mg, 0.31 mmol, 1 equiv), DIPEA (80 mg, 0.62 mmol, 2.00 equiv),EDCl (89.8 mg, 0.47 mmol, 1.50 equiv), HOBt (62.8 mg, 0.47 mmol, 1.50equiv), and Int-A2 (69.4 mg, 0.37 mmol, 1.20 equiv) in DMF (3 mL) wasstirred for 1 h at room temperature. After concentration, the residuewas purified by C18 reverse phase chromatography eluting with H₂O/ACN.The residue was further purified by Prep-HPLC yielding the titlecompound (28.1 mg, 16.94%) as a white solid. LCMS (ESI, m/z): 540.30[M+H]+, ¹H NMR (300 MHz, Methanol-d₄) δ 8.61 (d, J=0.8 Hz, 2H), 7.98 (s,1H), 4.09 (d, J=5.7 Hz, 1H), 3.99-3.92 (m, 4H), 3.84 (dd, J=5.2, 3 Hz,2H), 3.79-3.62 (m, 8H), 2.72 (d, J=5.9 Hz, 2H).

Example 604:5-[[(2S)-1-Hydroxy-3-(3-oxo-3-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of3-(3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy)propanoicacid (100 mg, 0.31 mmol, 1 equiv), DIEA (80 mg, 0.62 mmol, 2.00 equiv),EDCl (89.8 mg, 0.47 mmol, 1.50 equiv), HOBt (62.8 mg, 0.47 mmol, 1.50equiv), and Int-A18 (69.4 mg, 0.37 mmol, 1.20 equiv) in DMF (3 mL) wasstirred for 1 h at room temperature. After concentration, the residuewas purified by C18 reverse phase chromatography eluting with H₂O/ACN.The residue was further purified by Prep-HPLC yielding the titlecompound (27.9 mg, 16.85%) as a white solid. LCMS (ESI, m/z): 539.30[M+H]+, ¹H NMR (300 MHz, Methanol-d₄) δ 8.38 (s, 1H), 7.98 (s, 1H), 7.77(dd, J=9.0, 2.6 Hz, 1H), 6.91 (d, J=9.0 Hz, 1H), 4.14-4.04 (m, 1H),3.89-3.78 (m, 2H), 3.78-3.63 (m, 12H), 2.71 (d, J=6.0 Hz, 2H).

Example 605:(S)-6-[4-[3-[2-Cyclopropyl-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy]propanoyl]piperazin-1-yl]nicotinonitrile

Step 1:5-[[(1S)-1-cyclopropyl-2-hydroxyethyl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of (2S)-2-amino-2-cyclopropylethan-1-ol hydrochloride (1 g,7.27 mmol, 1 equiv), Int-A6 (2.45 g, 7.45 mmol, 1.03 equiv) and TEA (1.7mL) in EtOH (15 mL) was stirred overnight at 60° C. The resultingsolution was diluted with 200 mL of EtOAc and washed with 50 mL of NH₄Cland 50 mL of brine. The organic layer was dried over anhydrous sodiumsulfate and concentrated. The residue was applied onto a silica gelcolumn with EtOAc/petroleum ether (1:2) to give 2.2 g (76.94%) of thetitle compound as a solid. LCMS (ESI, m/z): 394.18 [M+H]⁺.

Step 2: Ethyl3-[(2S)-2-cyclopropyl-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy]propanoate

A solution of5-[[(1S)-1-cyclopropyl-2-hydroxyethyl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(2.1 g, 5.34 mmol, 1 equiv), ethyl prop-2-enoate (0.8 mL) and Cs₂CO₃ (2g, 6.14 mmol, 1.15 equiv) in ACN (15 mL) was stirred overnight at 35° C.The solids were filtered out. The resulting mixture was concentrated.The residue was applied onto a silica gel column with EtOAc/petroleumether (1:1). This resulted in 580 mg (crude) of the title compound as asolid. LCMS (ESI, m/z): 494.23 [M+H]⁺

Step 3: Ethyl3-[(2S)-2-cyclopropyl-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy]propanoate

A solution of ethyl3-[(2S)-2-cyclopropyl-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy]propanoate(550 mg, 1.11 mmol, 1 equiv) in HCl/dioxane (20 mL) was stirredovernight at RT. The resulting mixture was concentrated. The crudeproduct was purified by Prep-HPLC to give 300 mg (74.10%) of the titlecompound as a solid. LCMS (ESI, m/z): 364.15 [M+H]⁺.

Step 4:3-[(2S)-2-Cyclopropyl-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy]propanoicAcid

To a stirred solution of ethyl3-[(2S)-2-cyclopropyl-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy]propanoate(300 mg, 0.83 mmol, 1 equiv) in THF (9 mL) and H₂O (3 mL), LiOH.H₂O (140mg, 3.5 mmol, 4.21 equiv) was added. The resulting solution was stirredfor 5 h at room temperature. The pH value of the solution was adjustedto 1 with HCl (1 M). The resulting mixture was concentrated to give 260mg (crude) of the title compound as a solid. LCMS (ESI, m/z): 336.12[M+H]⁺.

Step 5:(S)-6-[4-[3-[2Cyclopropyl-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy]propanoyl]piperazin-1-yl]nicotinonitrile

To a stirred solution of3-[(2S)-2-cyclopropyl-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy]propanoicacid (130 mg, 0.39 mmol, 1.00 equiv) in DMF (10 mL), and Int-A4 (80 mg,0.43 mmol, 1.09 equiv), DIPEA (0.5 mL) and HATU (180 mg, 0.47 mmol, 1.2equiv) were added. The resulting solution was stirred for 2 h at roomtemperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN. The residue wasfurther purified by Prep-HPLC yielding the title compound (75.9 mg, 39%)as a white solid. LCMS (ESI, m/z): 506.25 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 12.40 (s, 1H), 8.51 (d, J=2.3 Hz, 1H), 7.97-7.81 (m, 2H),6.92 (d, J=9.1 Hz, 1H), 6.50-6.37 (m, 1H), 3.74-3.49 (m, 13H), 2.57 (t,J=6.4 Hz, 2H), 1.12-1.00 (m, 1H), 0.53-0.39 (m, 2H), 0.37-0.27 (m, 2H).

Example 606:(S)-5-[(1-Cyclopropyl-2-[3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl]propoxy]-ethyl]amino]-4-(trifluoromethyl)pyridazin-3(2H)-one

To a stirred solution of3-[(2S)-2-cyclopropyl-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy]propanoicacid (130 mg, 0.39 mmol, 1.00 equiv) in DMF (10 mL), and Int-A2 (80 mg,0.43 mmol, 1.09 equiv), DIPEA (0.5 mL) and HATU (180 mg, 0.47 mmol, 1.2equiv) were added. The resulting solution was stirred for 2 h at roomtemperature. After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN. The residue wasfurther purified by Prep-HPLC yielding the title compound (79.3 mg, 37%)as a white solid. LCMS (ESI, m/z): 550.25 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 12.40 (s, 1H), 8.73 (s, 2H), 7.88 (s, 1H), 6.51-6.38 (m, 1H),3.94-3.44 (m, 13H), 2.58 (t, J=6.5 Hz, 2H), 1.15-1.01 (m, 1H), 0.55-0.40(m, 2H), 0.38-0.25 (m, 2H).

Example 607:5-[[(2R,3R)-3-Methoxy-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)butan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1: (2R,3R)-2-amino-3-methoxybutan-1-ol

A solution of (2S,3R)-2-amino-3-methoxybutanoic acid (1 g, 7.51 mmol, 1equiv), diborane (15.0 mL, 1 M, 2 equiv) in THF (15 mL) was stirred for12 h at room temperature. The reaction was quenched by the addition of15 mL of methanol. The resulting mixture was concentrated, diluted with15 mL of water and washed with 2×30 ml of DCM. The organic layers werecombined and dried over Na₂SO₄. The resulting mixture was concentratedto afford 2.2 g (crude) of the title compound as colorless oil. LCMS(ESI, m/z): 120.09 [M+H]⁺

Step 2:5-[[(2R,3R)-1-hydroxy-3-methoxybutan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of (2R,3R)-2-amino-3-methoxybutan-1-ol (2.18 g, 18.29 mmol, 1equiv), Int-A6 (2.46 g, 7.48 mmol, 0.41 equiv), and TEA (3.7 g, 36.56mmol, 2.00 equiv) in ethanol (10 mL, 1.00 equiv) was stirred for 1 h at80° C. The resulting mixture was concentrated under vacuum. The residuewas applied onto a silica gel column eluting with EtOAc/petroleum ether(3/7) to afford 1.63 g (21.6%) of the title compound as yellow oil. LCMS(ESI, m/z): 412.18[M+H]⁺

Step 3: Methyl3-[(2R,3R)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate

A solution of5-[[(2R,3R)-1-hydroxy-3-methoxybutan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1.62 g, 3.94 mmol, 1 equiv), Cs₂CO₃ (2.6 g, 7.87 mmol, 2.00 equiv),methyl prop-2-enoate (1.7 g, 19.68 mmol, 5.00 equiv) in ACN (10 mL) wasstirred for 1 h at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (3/7) to afford 870 mg (44.4%)of the title compound as yellow oil. LCMS (ESI, m/z): 498.22[M+H]⁺

Step 4: Methyl3-[(2R,3R)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate

A solution of methyl3-[(2R,3R)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate(850 mg, 1.71 mmol, 1 equiv) in DCM (10 mL) and TFA (1 mL) was stirredfor 1 h at RT. The pH value of the solution was adjusted to 8 withethanolamine. The resulting solution was diluted with 20 mL of water andextracted with 4×20 mL of DCM. The organic layers combined and driedover Na₂SO₄. The resulting solution was concentrated under vacuum toafford 640 mg of the title compound as yellow oil. LCMS (ESI, m/z):368.14 [M+H]⁺

Step 5:3-[(2R,3R)-3-Methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoicAcid

A solution of methyl3-[(2R,3R)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate(620 mg, 1.69 mmol, 1 equiv), LiOH.H₂O (354.2 mg, 8.44 mmol, 5.00 equiv)in methanol (15 mL) and water (5 mL, 277.54 mmol, 164.43 equiv) wasstirred for 1 h at room temperature. After concentration, the pH valueof the solution was adjusted to 5 with HCl (1 M). The resulting solutionwas extracted with 5×25 mL of DCM. The organic layers combined and driedover Na₂SO₄. The resulting solution was concentrated under vacuum toafford 500 mg (84%) of the title compound as a yellow solid. LCMS (ESI,m/z): 354.12 [M+H]⁺

Step 6:5-[[(2R,3R)-3-methoxy-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)butan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of3-[(2R,3R)-3-methoxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoicacid (100 mg, 0.28 mmol, 1 equiv), DIPEA (109.7 mg, 0.85 mmol, 3 equiv),Int-A2 (76.0 mg, 0.28 mmol, 1 equiv), HATU (161.4 mg, 0.42 mmol, 1.5equiv) in DMF (3 mL) was stirred for 1 h at RT. The resulting solutionwas purified by C18 reverse phase chromatography eluting with H₂O/ACN.The residue was further purified by Prep-HPLC yielding the titlecompound (44.5 mg, 27.70%) as a white solid. LCMS (ESI, m/z): 568.47[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ: 12.49 (s, 1H), 8.74 (d, J=0.9 Hz,2H), 7.91 (s, 1H), 6.01 (dd, J=9.3, 4.8 Hz, 1H), 4.07 (d, J=7.3 Hz, 1H),3.83 (dt, J=19.5, 5.5 Hz, 4H), 3.70 (tt, J=9.3, 4.8 Hz, 2H), 3.54 (ddt,J=12.8, 6.3, 3.6 Hz, 7H), 3.27 (s, 3H), 2.60 (t, J=6.4 Hz, 2H), 1.11 (d,J=6.3 Hz, 3H).

Example 608:4-Bromo-5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]oxy]-2,3-dihydropyridazin-3-one

Step 1:1-[4-[5-(Trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]prop-2-en-1-one

A solution of Int-A2 (5 g), prop-2-enoyl prop-2-enoate (3 g), and TEA(6.7 g) in DCM (80 mL) was stirred for 1 h at RT. The resulting solutionwas concentrated under reduced pressure and then the residue was appliedonto a silica gel column eluting with EtOAc/petroleum ether (38:62) toafford 4.2 g of the title compound as a white solid. LCMS: [M+H]⁺287.10.

Step 2:3-[(2S)-2-(Benzyloxy)propoxy]-1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propan-1-one

A solution of1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]prop-2-en-1-one(Int-A21: 1 g. 3.49 mmol, 1 equiv), Cs₂CO₃ (3.4 g, 10.44 mmol. 2.99equiv), and (2S)-2-(benzyloxy)propan-1-ol (1.74 g, 0.01 mmol) in ACN (50mL) was stirred for 36 h at 80° C. The solids were filtered and then theresulting solution was concentrated under vacuum. The residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(1:1) to afford 480 mg (30%) of the title compound as a brown oil. LCMS:[M+H]⁺ 453.20.

Step 3:3-[(2S)-2-Hydroxypropoxy]-1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propan-1-one

A solution of3-[(2S)-2-(benzyloxy)propoxy]-1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propan-1-one(460 mg, 1.02 mmol, 1 equiv) in DCM (10 mL) was stirred for 10 min at 0°C. BCl₃ in DCM (3 mL, 3.0 equiv) was then added and the resultingsolution was stirred for another 3 h at 0° C. The resulting solution wasconcentrated under vacuum and was purified by Flash-Prep-HPLC with thefollowing conditions (IntelFlash-1): Column, C18 silica gel; mobilephase, ACN:H₂O=5.95 increasing to ACN:H₂O=47.53 within 25 min; Detector,UV 254 nm. The title compound was obtained by concentration underreduced pressure to afford 190 mg (52%) of the title compound as a whitesolid. LCMS: [M+H]⁺ 363.16.

Step 4:4-Bromo-5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]oxy]-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of3-[(2S)-2-hydroxypropoxy]-1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propan-1-one(170 mg, 0.47 mmol, 1 equiv), ACN (8 mL, 152.20 mmol, 324.41 equiv),Cs₂CO₃ (458 mg, 1.41 mmol, 3.00 equiv), and Int-A8 (538 mg, 1.40 mmol,2.99 equiv) was stirred for 10 h at 80° C. The solids were filtered andthen the residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (2:3) to afford 150 mg (48%) of the title compoundas a brown oil LCMS: [M+H]⁺ 665.17[M+H]⁺, 667.17[M+H]⁺.

Step 5:4-Bromo-5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]oxy]-2,3-dihydropyrimidin-3-one

A solution of4-bromo-5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]oxy]-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(120 mg, 0.18 mmol, 1 equiv), DCM (3 mL), and TFA (0.6 mL, 8.08 mmol,44.80 equiv) was stirred for 1.5 h at RT The resulting mixture wasconcentrated under vacuum and was purified by Flash-Prep-HPLC. The crudeproduct was further purified by Chiral-Prep-HPLC yielding the titlecompound (10.8 mg, 11%) as a white solid. LCMS: [M+H]⁺ 535.10, 537.10.¹H NMR (300 MHz, Methanol-d₄) δ 8.58 (s, 2H), 8.05 (s, 1H), 5.02 (td,J=6.6, 3.2 Hz, 1H), 3.89 (q, J=5.6, 5.2 Hz, 4H), 3.83-3.70 (m, 1H),3.74-3.57 (m, 7H), 2.65 (t, J=5.9 Hz, 2H), 1.36 (d, J=6.3 Hz, 3H).

Example 609:4-Bromo-5-[[(2S)-1-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]propan-2-yl]oxy]-2,3-dihydropyridazin-3-one

Step 1:3-[(2S)-2-(Benzyloxy)propoxy]-1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]propan-1-one

A solution of 1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]but-3-en-1-one(1 g, 3.75 mmol, 1 equiv), (2S)-2-(benzyloxy)propan-1-ol (1.2 g, 7.50mmol, 2.0 equiv), and Cs₂CO₃ (2.4 g, 7.50 mmol, 2.0 equiv) in ACN (10mL) was stirred for 16 h at 80° C. The solids were filtered and theresulting mixture was concentrated. The residue was applied onto asilica gel column with EtOAc/petroleum ether (2:3) to afford 894 mg(57%) of the title compound as a yellow oil. LCMS: [M+H]⁺ 419.20.

Step 2:1-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]-3-[(2S)-2-hydroxypropoxy]propan-1-one

To a solution of3-[(2S)-2-(benzyloxy)propoxy]-1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]propan-1-one(874 mg, 2.09 mmol, 1 equiv) in DCM (3 mL) was added BCl₃ (10 mL) at 0°C. The resulting solution was stirred for 1 h at 0° C. and the resultingsolution was concentrated under vacuum. The residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN to afford 1.04 g(53%) of the title compound as a yellow oil. LCMS: [M+H]⁺ 329.15.

Step 3:4-Bromo-5-[[(2S)-1-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]propan-2-yl]oxy]-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of1-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-[(2S)-2-hydroxypropoxy]propan-1-one(406 mg, 1.23 mmol, 1 equiv), Int-A8 (948.7 mg, 2.47 mmol, 2.0 equiv),and Cs₂CO₃ (804.6 mg, 2.47 mmol, 2.0 equiv) in ACN (10 mL) was stirredfor 8 h at 60° C. The resulting solids were filtered and the resultingmixture was concentrated. The residue was applied onto a silica gelcolumn with EtOAc/petroleum ether (1:1) to afford 260 mg (33%) of thetitle compound as a yellow oil. LCMS: [M+H]⁺ 631.14, 633.14.

Step 4:4-Bromo-5-[[(2S)-1-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]propan-2-yl]oxy]-2,3-dihydropyridazin-3-one

A solution of4-bromo-5-[[(2S)-1-[3-[4-(5-chloropyrimidin-2-yl)piperazin-1-yl]-3-oxopropoxy]propan-2-yl]oxy]-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(260 mg, 0.41 mmol, 1 equiv), DCM (10 L), and TFA (2 mL) was stirred for1 h at RT. The resulting solution was concentrated under vacuum and theresidue was purified by Prep-HPLC yielding the title compound (39.9 mg,19%) as a white solid. LCMS: [M+H]⁺ 500.95, 502.95. ¹H NMR (300 MHz,CD₃OD-d₄) δ 8.32 (s, 2H), 8.06 (s, 1H), 5.03 (td, J=6.6, 3.3 Hz, 1H),3.93-3.57 (m, 12H), 2.66 (t, J=5.9 Hz, 2H), 1.38 (d, J=6.3 Hz, 3H).

Example 610:5-[[(2R,3R)-3-Hydroxy-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)butan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1:(2S,3R)-3-Hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]butanoicAcid

A solution of (2S,3R)-2-amino-3-hydroxybutanoic acid (1190 mg, 9.99mmol, 1 equiv), TEA (2021.8 mg, 19.98 mmol, 2 equiv), and Int-A6 (3284.6mg, 9.99 mmol, 1 equiv) in EtOH (20 mL) was stirred for 1 h at RT. Afterconcentration under reduced pressure, the crude material was purified byC18 reverse phase chromatography eluting with H₂O/CH₃CN to afford 900 mg(22%) of the title compound as a yellow oil. LCMS: [M+H]⁺ 411.45.

Step 2:5-[[(2R,3R)-1,3-Dihydroxybutan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of(2S,3R)-3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]butanoicacid (900 mg, 2.19 mmol, 1 equiv) in BH₃-THF (10 mL) was stirred for 2 hat 0° C. The reaction was then quenched by the addition of 100 mL ofwater/ice and the resulting solution was extracted with 3×100 mL ofEtOAc. The organic layers were concentrated, and then the resultingsolution was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN to afford 776 mg (89%) of the title compound as a yellow oil.LCMS: [M+H]⁺ 397.47.

Step 3: Methyl3-[(2R,3R)-3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate

A solution of5-[[(2R,3R)-1,3-dihydroxybutan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(776 mg, 1.95 mmol, 1 equiv), Cs₂CO₃ (1272.2 mg, 3.90 mmol, 2.0 equiv),methyl prop-2-enoate (336.2 mg, 3.90 mmol, 2.0 equiv) and ACN (10 mL)was stirred for 1 h at RT. The solids were filtered and the resultingsolution was concentrated under vacuum. The resulting solution waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN toafford 450 mg (48%) of the title compound as a yellow oil. LCMS: [M+H]⁺483.55.

Step 4: Methyl3-[(2R,3R)-3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate

A solution of methyl3-[(2R,3R)-3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate(450 mg, 0.93 mmol, 1 equiv) and TFA (1 mL) in DCM (5 mL) was stirredfor 1 h at RT. The resulting solution was concentrated under vacuum toafford 650 mg of the title compound as a yellow oil. LCMS: [M+H]⁺353.29.

Step 5:3-[(2R,3R)-3-Hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoicAcid

A solution of methyl3-[(2R,3R)-3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate(650 mg, 1.84 mmol, 1 equiv), LiOH (220.3 mg, 9.20 mmol, 5.0 equiv) inH₂O (1 mL):MeOH (5 mL) was stirred for 1 h at RT. The pH value of thesolution was adjusted to 2 with HCl (1 M) and then the resultingsolution was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN to afford 120 mg (19%) of the title compound as a yellow oil.LCMS: [M+H]⁺ 339.27.

Step 6:5-[[(2R,3R)-3-Hydroxy-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)butan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of3-[(2R,3R)-3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoicacid (120 mg, 0.35 mmol, 1 equiv), HATU (134.5 mg, 0.35 mmol, 1.0equiv), Int-A2 (82.1 mg, 0.35 mmol, 1 equiv), and DIPEA (91.4 mg, 0.71mmol, 2.0 equiv) in DMF (2 mL) was stirred for 1 h at RT and then theresulting solution was purified by C18 reverse phase chromatographyeluting with H₂O/CH₃CN. The residue was further purified by Prep-HPLCyielding the title compound (56.7 mg, 29%) as a white solid. LCMS:[M+H]⁺ 554.25. ¹H NMR (300 MHz, Methanol-d4) δ 8.62 (s, 2H), 7.96 (s,1H), 4.08-3.80 (m, 6H), 3.85-3.80 (m, 2H), 3.79-3.55 (m, 6H), 2.70 (t,J=5.9 Hz, 2H), 1.21 (d, J=6.3 Hz, 3H).

Example 611:5-[[(2R,3S)-3-Hydroxy-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)butan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

Step 1:(2S,3S)-3-Hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]butanoicAcid

A solution of (2S,3S)-2-amino-3-hydroxybutanoic acid (2.38 g, 0.02 mmol,1 equiv), TEA (4.0 g, 0.04 mmol, 2 equiv), Int-A6 (6.6 g, 0.02 mmol, 1equiv) in EtOH (50 mL) was stirred for 1 h at RT. After concentrationunder reduced pressure, the crude residue was purified by C18 reversephase chromatography eluting with H₂O/CH₃CN to afford 2.1 g (26%) of thetitle compound as a yellow oil. LCMS: [M+H]⁺ 411.45.

Step 2:5-[[(2R,3S)-1,3-Dihydroxybutan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of(2S,3S)-3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]butanoicacid (2 g, 4.86 mmol, 1 equiv) in BH₃-THF (50 mL) was stirred for 2 h at0° C. The reaction was then quenched by the addition of 100 mL ofwater/ice and the resulting solution was extracted with 3×100 mL ofEtOAc. The organic layers were concentrated under reduced pressure andthen the resulting solution was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford 1.5 g (78%) of the titlecompound as a yellow oil. LCMS: [M+H]⁺ 397.47.

Step 3: Methyl3-[(2R,3S)-3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate

A solution of5-[[(2R,3S)-1,3-dihydroxybutan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1500 mg, 3.774 mmol, 1 equiv), Cs₂CO₃ (2459.20 mg, 7.548 mmol, 2.0equiv), and methyl prop-2-enoate (487.34 mg, 5.661 mmol, 1.5 equiv) inMeCN (50 mL) was stirred for 1 h at RT. The solids were filtered and theresulting solution was concentrated under vacuum to afford the crudeproduct which was purified by C18 reverse phase chromatography elutingwith H₂O/CH₃CN to afford 720 mg (39%) of the title compound as a yellowoil. LCMS: [M+H]⁺ 483.55.

Step 4: Methyl3-[(2R,3S)-3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate

A solution of methyl3-[(2R,3S)-3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate(720 mg, 1.489 mmol, 1 equiv) and TFA (1 mL) in DCM (5 mL) was stirredfor 1 h at RT. The resulting solution was concentrated under vacuum toafford 1 g of the title compound as a yellow oil. LCMS: [M+H]⁺ 353.29.

Step 5:3-[(2R,3S)-3-Hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoicAcid

A solution of methyl3-[(2R,3S)-3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoate(1000 mg, 2.830 mmol, 1 equiv), and LiOH (338.92 mg, 14.152 mmol, 5equiv) in H₂O (1 mL)/MeOH (5 mL) was stirred for 1 h at RT. The pH valueof the solution was adjusted to 2 with HCl (1M) and then the crudeproduct was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN to afford 190 mg (20%) of the title compound as a yellow oil.LCMS: [M+H]⁺ 339.27.

Step 6:5-[[(2R,3S)-3-Hydroxy-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)butan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

A solution of3-[(2R,3S)-3-hydroxy-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]butoxy]propanoicacid (120 mg, 0.35 mmol, 1 equiv), HATU (134.5 mg, 0.35 mmol, 1.0equiv), Int-A2 (82.1 mg, 0.35 mmol, 1 equiv), and DIPEA (91.4 mg, 0.71mmol, 2.0 equiv) in DMF (2 mL) was stirred for 1 h at RT and then thecrude product was purified by C18 reverse phase chromatography elutingwith H₂O/CH₃CN. The residue was further purified by Prep-HPLC yieldingthe title compound (32 mg, 16%) as a white solid. LCMS: [M+H]⁺ 554.25.¹H NMR (300 MHz, Methanol-d4) δ 8.61 (s, 2H), 7.99 (s, 1H), 4.08-3.91(m, 6H), 3.97-3.79 (m, 3H), 3.79-3.59 (m, 5H), 2.69 (t, J=5.9 Hz, 2H),1.24 (d, J=6.4 Hz, 3H).

Example 612 Isomer A:6-(4-[2-[(2R,5S)-5-[(1R)-2-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 612 Isomer B:6-(4-[2-[(2R,5S)-5-[(1S)-2-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 612 Isomer C:6-(4-[2-[(2R,5R)-5-[(1S)-2-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand Example 612 Isomer D:6-(4-[2-[(2S,5S)-5-[(1R)-2-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

Step 1: Tert-butyl1-(hydroxymethyl)-2,3-dihydro-1H-isoindole-2-carboxylate

A solution of2-[(tert-butoxy)carbonyl]-2,3-dihydro-1H-isoindole-1-carboxylic acid(3.6 g, 13.67 mmol, 1 equiv) and B₂H₆/THF (27 mL) in THF (40 mL) wasstirred for 12 h at RT. The resulting solution was quenched by theaddition of 30 mL of NH₄Cl solution and extracted with 3×50 mL of EtOAc.The organic layers were combined and dried over Na₂SO₄. The reactionmixture was concentrated under vacuum to afford 3.9 g of the titlecompound as a brown solid. LCMS: [M+H]⁺ 250.14.

Step 2: Tert-butyl 1-formyl-2,3-dihydro-1H-isoindole-2-carboxylate

A solution of tert-butyl1-(hydroxymethyl)-2,3-dihydro-1H-isoindole-2-carboxylate (3.9 g, 15.64mmol, 1 equiv) and Dess-Martin (10.1 g, 23.81 mmol, 1.52 equiv) in DCM(40 mL) was stirred for 12h at RT. The reaction was quenched by theaddition of 40 mL of Na₂SO₃/H₂O. The resulting solution was extractedwith 3×50 mL of DCM and the organic layers combined, and washed with2×50 mL of NaHCO₃. The organic layers were combined and dried overNa₂SO₄ and concentrated under reduced pressure. The residue was appliedonto a silica gel column eluting with EtOAc/petroleum ether (1/9) toafford 830 mg (21%) of the title compound as a yellow oil. LCMS: [M+H]⁺248.12.

Step 3: Tert-butyl1-(1-hydroxypent-4-en-1-yl)-2,3-dihydro-1H-isoindole-2-carboxylate

A solution of tert-butyl 1-formyl-2,3-dihydro-1H-isoindole-2-carboxylate(830 mg, 3.36 mmol, 1 equiv), bromo(but-3-en-1-yl)magnesium (5.0 mL,5.00 mmol, 1.49 equiv) in THF (20 mL) was stirred for 1 h under theatmosphere of nitrogen at RT. The resulting solution was quenched by theaddition of 20 mL of water and extracted with 3×30 mL of EtOAc. Theresulting mixture was concentrated under vacuum to afford 945 mg (93%)of the title compound as a yellow oil. LCMS: [M+H]⁺ 304.18.

Step 4: Tert-butyl1-[(4Z)-1-hydroxy-6-methoxy-6-oxohex-4-en-1-yl]-2,3-dihydro-1H-isoindole-2-carboxylate

A solution of tert-butyl1-(1-hydroxypent-4-en-1-yl)-2,3-dihydro-1H-isoindole-2-carboxylate (945mg, 3.11 mmol, 1 equiv), methyl prop-2-enoate (1340.7 mg, 15.57 mmol,5.00 equiv), and Grubbs 2nd generation catalyst (26.4 mg, 0.03 mmol,0.01 equiv) in DCM (25 mL) was stirred for 1.5h under a nitrogenatmosphere at 45° C. The reaction mixture was concentrated under vacuumand the residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1/9) to afford 930 mg (83%) of the title compoundas a yellow oil. LCMS: [M+H]⁺ 362.19.

Step 5: Tert-butyl1-[5-(2-methoxy-2-oxoethyl)oxolan-2-yl]-2,3-dihydro-1H-isoindole-2-carboxylate

A solution of tert-butyl1-[(4Z)-1-hydroxy-6-methoxy-6-oxohex-4-en-1-yl]-2,3-dihydro-1H-isoindole-2-carboxylate(930 mg, 2.57 mmol, 1 equiv) and sodium hydride (185.2 mg, 7.72 mmol,3.00 equiv) in THF (20 mL) was stirred for 12h at RT. The reaction wasthen quenched by the addition of water and the resulting solution wasextracted with 4×50 mL of EtOAc and the organic layers combined andconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with EtOAc/petroleum ether (15/85) to afford 630 mg (68%)of the title compound as a yellow oil. LCMS: [M+H]⁺ 362.19.

Step 6:2-(5-[2-[(Tert-butoxy)carbonyl]-2,3-dihydro-1H-isoindol-1-yl]oxolan-2-yl)aceticAcid

A solution of tert-butyl1-[5-(2-methoxy-2-oxoethyl)oxolan-2-yl]-2,3-dihydro-1H-isoindole-2-carboxylate(610 mg, 1.69 mmol, 1 equiv) and LiOH.H₂O (354.1 mg, 8.44 mmol, 5.00equiv) in MeOH (15 mL) and water (5 mL) was stirred for 2 h at RT. Theresulting mixture was concentrated and the pH of the solution wasadjusted to 6 with HCl (1M) and extracted with 5×30 mL of DCM. Theorganic layers were combined and dried over Na₂SO₄. The resultingmixture was concentrated under vacuum to afford 520 mg (89%) of thetitle compound as a yellow solid. LCMS: [M+H]⁺ 348.17.

Step 7: Tert-butyl1-(5-[2-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl)-2,3-dihydro-1H-isoindole-2-carboxylate

A solution of2-(5-[2-[(tert-butoxy)carbonyl]-2,3-dihydro-1H-isoindol-1-yl]oxolan-2-yl)aceticacid (500 mg, 1.44 mmol, 1 equiv), DIPEA (558.0 mg, 4.32 mmol, 3.00equiv), Int-A4 (323.4 mg, 1.44 mmol, 1 equiv), HATU (820.9 mg, 2.16mmol, 1.5 equiv) in DMF (5 mL) was stirred for 1 h at RT. The residuewas purified by C18 reverse phase chromatography eluting with H₂O/CH₃CNto afford 670 mg (90%) of the title compound as an off-white solid.LCMS: [M+H]⁺ 518.27.

Step 8:6-(4-[2-[5-(2,3-Dihydro-1H-isoindol-1-yl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileHydrochloride

A solution of tert-butyl1-(5-[2-[4-(5-cyanopyridin-2-yl)piperazin-1-yl]-2-oxoethyl]oxolan-2-yl)-2,3-dihydro-1H-isoindole-2-carboxylate(620 mg, 1.20 mmol, 1 equiv) in HCl/dioxane (10 mL) was stirred for 30min at RT. The resulting mixture was concentrated under vacuum to afford520 mg (96%) of the title compound as a yellow solid. LCMS: [M+H]⁺418.22.

Step 9:6-[4-[2-(5-[2-[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]oxolan-2-yl)acetyl]piperazin-1-yl]pyridine-3-carbonitrile

A solution of6-(4-[2-[5-(2,3-dihydro-1H-isoindol-1-yl)oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrilehydrochloride (520 mg, 1.15 mmol, 1 equiv), Int-A6 (376.6 mg, 1.15 mmol,1 equiv) and TEA (231.8 mg, 2.29 mmol, 2 equiv) in EtOH (20 mL) wasstirred for 1 h at 80° C. The reaction mixture was concentrated undervacuum and the residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (6/4) to afford 730 mg (90%) of the title compoundas a yellow solid. LCMS: [M+H]⁺ 710.30.

Step 10:6-(4-[2-[(2R,5S)-5-[(1R)-2-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile,6-(4-[2-[(2R,5S)-5-[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile,6-(4-[2-[(2R,5R)-5-[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrileand6-(4-[2-[(2S,5S)-5-[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]oxolan-2-yl]acetyl]piperazin-1-yl)pyridine-3-carbonitrile

A solution of6-[4-[2-(5-[2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]oxolan-2-yl)acetyl]piperazin-1-yl]pyridine-3-carbonitrile(710 mg, 1.00 mmol, 1 equiv) in TFA (2 mL) and DCM (10 mL) was stirredfor 1.5 h at RT After concentration, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN. The residue wasfurther purified by Prep-HPLC and Chiral-Prep-HPLC (ChiralpakCellulose-SB, 3 μm, 0.46×15 cm column, eluting with a gradient of MtBE(0.1% DEA):EtOH=80:20, at a flow rate of 1 mL/min) yielding the titlecompounds as white solids and with the stereochemistry arbitrarilyassigned.

Example 612 Isomer A

LCMS: [M+H]⁺ 580.57, ¹H NMR (400 MHz, DMSO-d₆) δ 12.48 (s, 1H), 8.52 (d,J=2.3 Hz, 1H), 8.29 (s, 1H), 7.89 (dd, J=9.1, 2.4 Hz, 1H), 7.44-7.36 (m,2H), 7.36-7.30 (m, 2H), 6.93 (d, J=9.3 Hz, 1H), 5.91-5.89 (d, J=5.8 Hz,1H), 5.05-5.02 (m, 1H), 4.45 (d, J=14.7 Hz, 1H), 4.17 (p, J=6.4 Hz, 1H),3.99 (q, J=6.8 Hz, 1H), 3.69-3.68 (m, 4H), 3.63-3.53 (m, 4H), 2.69 (dd,J=15.3, 6.0 Hz, 1H), 2.43 (dd, J=15.4, 6.8 Hz, 1H), 2.10-1.94 (m, 1H),1.88 (dq, J=13.8, 7.0, 6.6 Hz, 1H), 1.71 (dq, J=15.5, 7.8 Hz, 1H),1.56-1.43 (m, 1H). tR=4.821 min

Example 612 Isomer B

LCMS: [M+H]⁺ 580.57 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 12.45 (s, 1H),8.50 (d, J=2.3 Hz, 1H), 8.24 (s, 1H), 7.87 (dd, J=9.1, 2.4 Hz, 1H),7.43-7.33 (m, 2H), 7.32-7.22 (m, 2H), 6.89 (d, J=9.1 Hz, 1H), 5.90 (d,J=6.0 Hz, 1H), 5.01 (d, J=14.8 Hz, 1H), 4.43 (d, J=14.8 Hz, 1H), 4.25(t, J=7.2 Hz, 1H), 4.13 (q, J=6.7 Hz, 1H), 3.65-3.62 (m, 2H), 3.34-3.28(m, 6H), 2.72-2.62 (m, 1H), 2.41 (dd, J=14.9, 5.7 Hz, 1H), 2.07-2.05 (m,1H), 1.98 (s, 1H), 1.76 (p, J=8.8 Hz, 1H), 1.56-1.43 (m, 1H). tR=6.334min.

Chiral-Prep-HPLC purification by ((R,R)-Whelk, 3.5 μm, 0.46×15 cmcolumn, eluting with a gradient of MtBE (0.1% DEA):EtOH=90:10, at a flowrate of 1 mL/min) afforded isomer C and isomer D as an arbitraryassignment of stereochemistry.

Example 612 Isomer C

LCMS: [M+H]⁺ 580.57, ¹H NMR (400 MHz, DMSO-d₆) δ 12.48 (s, 1H), 8.51 (d,J=2.3 Hz, 1H), 8.29 (s, 1H), 7.89 (dd, J=9.1, 2.4 Hz, 1H), 7.44-7.36 (m,2H), 7.36-7.28 (m, 2H), 6.93 (d, J=9.3 Hz, 1H), 5.91 (d, J=5.8 Hz, 1H),5.04 (d, J=14.7 Hz, 1H), 4.45 (d, J=14.8 Hz, 1H), 4.17 (p, J=6.5 Hz,1H), 3.99 (q, J=6.8 Hz, 1H), 3.69 (d, J=5.3 Hz, 2H), 3.63 (d, J=5.4 Hz,2H), 3.53 (t, J=5.3 Hz, 4H), 2.69 (dd, J=15.4, 6.0 Hz, 1H), 2.43 (dd,J=15.5, 6.9 Hz, 1H), 2.10-1.94 (m, 1H), 1.88 (dq, J=13.6, 6.6 Hz, 1H),1.71 (dq, J=15.7, 7.7 Hz, 1H), 1.56-1.43 (m, 1H). tR=2.826 min.

Example 612 Isomer D

LCMS: [M+H]⁺ 580.57, ¹H NMR (400 MHz, DMSO-d₆) δ 12.48 (s, 1H), 8.51 (d,J=2.3 Hz, 1H), 8.29 (s, 1H), 7.89 (dd, J=9.1, 2.4 Hz, 1H), 7.44-7.36 (m,2H), 7.36-7.28 (m, 2H), 6.93 (d, J=9.3 Hz, 1H), 5.91 (d, J=5.8 Hz, 1H),5.04 (d, J=14.7 Hz, 1H), 4.45 (d, J=14.8 Hz, 1H), 4.17 (p, J=6.5 Hz,1H), 3.99 (q, J=6.8 Hz, 1H), 3.69 (d, J=5.3 Hz, 2H), 3.63 (d, J=5.4 Hz,2H), 3.53 (t, J=5.3 Hz, 4H), 2.69 (dd, J=15.4, 6.0 Hz, 1H), 2.43 (dd,J=15.5, 6.9 Hz, 1H), 2.10-1.94 (m, 1H), 1.88 (dq, J=13.6, 6.6 Hz, 1H),1.71 (dq, J=15.7, 7.7 Hz, 1H), 1.56-1.43 (m, 1H). tR=3.640 min.

Example 613:(S)-5-((1-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrazin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

Step 1: Tert-butyl4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-carboxylate

A solution of 2-chloro-5-(trifluoromethyl)pyrazine (1.5 g, 8.22 mmol, 1equiv), K₂CO₃ (2.27 g, 16.4 mmol, 2 equiv), and tert-butylpiperazine-1-carboxylate (1.53 g, 8.22 mmol, 1 equiv) in NMP (15 mL) wasstirred for 1 h at 80° C. followed by the addition of 50 mL of water.The resulting solids were collected by filtration to afford 2.5 g(91.5%) of the title compound. LCMS: [M+H]⁺ 332.

Step 2: 2-(Piperazin-1-yl)-5-(trifluoromethyl)pyrazine

A solution of tert-butyl4-[5-(trifluoromethyl)pyrazin-2-yl]piperazine-1-carboxylate (2.5 g, 7.52mmol, 1 equiv) in HCl (gas) in 1,4-dioxane (20 mL) was stirred for 1 hat RT. The solids were collected by filtration to afford 1 g (57.3%) oftitle compound as a white solid. LCMS: [M+H]⁺ 232.

Step 3:(S)-5-((1-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrazin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of Int-A13 (151.4 mg, 0.490 mmol, 1.4 equiv), DIPEA (180.8mg, 1.40 mmol, 4 equiv), HATU (172.9 mg, 0.455 mmol, 1.3 equiv), and2-(piperazin-1-yl)-5-(trifluoromethyl)pyrazine (81.2 mg, 0.350 mmol, 1equiv) in DMF (2 mL) was stirred for 1 h at RT. The crude product waspurified by Prep-HPLC (YMC-Actus Triart C18, 5 μm, 30×250 cm column,eluting with a gradient of water 10 mmol/L NH₄HCO₃ in ACN) to afford73.9 mg (40.4%) of title compound as a white solid. LCMS: [M+H]⁺ 524.24.¹H NMR (300 MHz, Methanol-d₄) δ 8.43 (s, 1H), 8.30 (s, 1H), 7.96 (s,1H), 4.18 (q, J=6.2 Hz, 1H), 3.82-3.76 (m, 10H), 3.64 (dd, J=9.7, 3.9Hz, 1H), 3.52 (dd, J=9.7, 6.8 Hz, 1H), 2.71 (t, J=5.9 Hz, 2H), 1.27 (d,J=6.6 Hz, 3H).

Example 614 Isomer A:5-(((S)-2-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)-1-((S)-tetrahydrofuran-3-yl)ethyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-oneand Example 614 Isomer B:5-(((R)-2-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)-1-((R)-tetrahydrofuran-3-yl)ethyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-oneand Example 614 Isomer C:5-(((S)-2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)-1-((R)-tetrahydrofuran-3-yl)ethyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-oneand Example 614 Isomer D:5-(((R)-2-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)-1-((S)-tetrahydrofuran-3-yl)ethyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

Step 1:5-((2-Hydroxy-1-(tetrahydrofuran-3-yl)ethyl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one

A solution of 2-amino-2-(tetrahydrofuran-3-yl)ethan-1-ol (2 g, 15.25mmol, 1 equiv), Int-A6 (5.0 g, 15.25 mmol, 1.0 equiv), and TEA (3.1 g,30.5 mmol, 2.0 equiv) in EtOH (20 mL) was stirred for 1 h at 60° C.After concentration under reduced pressure, the residue was purified bysilica gel chromatography eluting with EtOAc/petroleum ether to afford2.5 g of title compound as a yellow oil. LCMS: [M+H]⁺ 424.18.

Step 2: Methyl3-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)-2-(tetrahydrofuran-3-yl)ethoxy)propanoate

A solution of5-((2-hydroxy-1-(tetrahydrofuran-3-yl)ethyl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one(1.3 g, 3.07 mmol, 1 equiv), Cs₂CO₃ (2.0 g, 6.14 mmol, 2.0 equiv), andmethyl acrylate (0.5 g, 6.14 mmol, 2.0 equiv) in CH₃CN (10 mL) wasstirred for 3 h at RT. The solid was filtered and the resulting filtratewas concentrated under reduced pressure. The resulting crude residue waspurified by reverse phase column chromatography eluting with water/CH₃CNto afford 128 mg of title compound as a yellow oil. LCMS: [M+H]⁺ 510.22.

Step 3:3-(2-((6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)-2-(tetrahydrofuran-3-yl)ethoxy)propanoicAcid

A solution of methyl 3-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)-2-(tetrahydrofuran-3-yl)ethoxy)propanoate(128 mg, 0.25 mmol, 1 equiv) and TFA (1 mL) in DCM (5 mL) was stirredfor 1 h at RT followed by concentration under reduced pressure to affordmethyl3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)-2-(tetrahydrofuran-3-yl)ethoxy)propanoate(68 mg, 0.18 mmol, 1 equiv), to which was added LiOH (21.5 mg, 0.90mmol, 5.0 equiv), and water (0.4 mL) in MeOH (2 mL). The resultingmixture was stirred for 4 h at RT, concentrated under reduced pressure,and the pH value of the solution was adjusted to 5 with HCl (1 mol/mL).The crude product was purified by C18 reverse phase columnchromatography eluting with water/CH₃CN to afford 40 mg of titlecompound as an oil. LCMS: [M+H]⁺ 366.12.

Step 4:5-(((S)-2-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)-1-((S)-tetrahydrofuran-3-yl)ethyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-oneand5-(((R)-2-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)-1-((R)-tetrahydrofuran-3-yl)ethyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-oneand5-(((S)-2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)-1-((R)-tetrahydrofuran-3-yl)ethyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-oneand5-(((R)-2-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)-1-((S)-tetrahydrofuran-3-yl)ethyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of3-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)-2-(tetrahydrofuran-3-yl)ethoxy)propanoicacid (40 mg, 0.109 mmol, 1 equiv), DIPEA (28.3 mg, 0.219 mmol, 2.0equiv), HATU (41.63 mg, 0.109 mmol, 1.0 equiv), and Int-A2 (30.51 mg,0.131 mmol, 1.2 equiv) in DMF (2 mL) was stirred for 40 minutes at RT.The resulting solution was diluted with 5 mL of water, extracted with3×10 mL of EtOAc, and the organic layers were combined. Afterconcentration under reduced pressure, the crude product was purified byC18 reverse phase column chromatography eluting with water/CH₃CN. Theracemic compound was then separated by Chiral-Prep-HPLC (CHIRALPAK IC, 5μm, 2×25 cm column, eluting with a gradient of Hexanes:DCM (3:1) in 10mM NH₃/EtOH mobile phase at a flow rate of 20 mL/min). Thestereochemistry of the four enantiomers was arbitrarily assigned.

Example 614 Isomer A-C

LCMS: [M+H]⁺ 580.10

Example 614 Isomer D:5-(((R)-2-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)-1-((S)-tetrahydrofuran-3-yl)ethyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

LCMS: [M+H]⁺ 580.10, ¹H NMR (300 MHz, Methanol-d₄) δ 8.65-8.58 (d, J=0.9Hz, 2H), 7.99 (s, 1H), 3.99-3.86 (m, 6H), 3.88-3.54 (m, 11H), 2.70 (d,J=5.9 Hz, 2H), 2.58 (m, 1H), 2.09 (m, 1H), 1.79-1.68 (m, 1H).

Example 615:(S)-5-((1-((3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)amino)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

Step 1:(S)-3-((2-Hydroxypropyl)amino)-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propan-1-one

A solution of (S)-1-aminopropan-2-ol (1 g, 13.3 mmol, 1 equiv) andInt-A21 (3.81 g, 13.3 mmol, 1 equiv) in MeOH (50 mL) was stirred for 4 hat 60° C. The resulting solution was concentrated under reduced pressureand the residue was purified by Prep-HPLC eluting with H₂O/CH₃CN toafford 3.2 g (69.2%) of title compound as a white solid. LCMS: [M+H]⁺362.17.

Step 2: Tert-butyl(S)-(2-hydroxypropyl)(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)carbamate

A solution of(S)-3-((2-hydroxypropyl)amino)-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propan-1-one(3.2 g, 8.855 mmol, 1 equiv), di-tert-butyl dicarbonate (1.93 g, 8.86mmol, 1 equiv) and TEA (1.79 g, 17.7 mmol, 2.0 equiv) in DCM (50 mL) wasstirred for 1 h at RT. The resulting solution was concentrated underreduced pressure, and the residue was purified by Prep-HPLC eluting withH₂O/CH₃CN to afford 4.1 g title compound as a white solid. LCMS: [M+H]⁺462.22.

Step 3: Tert-butyl(S)-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propyl)(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)carbamate

A solution of tert-butyl(S)-(2-hydroxypropyl)(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)carbamate(4 g, 8.7 mmol, 1 equiv), Int-A20 (2.76 g, 8.7 mmol, 1.0 equiv) andtert-BuONa (1.25 g, 13.0 mmol, 1.5 equiv) in DCM (100 mL) was stirredfor 1 h at 0° C. The resulting solution was diluted with 200 mL ofwater, extracted with 3×100 mL of EtOAc, and the organic layer wascombined and concentrated under reduced pressure. The residue waspurified by Prep-HPLC eluting with H₂O/CH₃CN to afford 4 g (62.1%) oftitle compound as a yellow solid. LCMS: [M+H]⁺ 744.29.

Step 4:(3)-5-((1-((3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)amino)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of tert-butyl(S)-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propyl)(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)carbamate(500 mg, 0.672 mmol, 1 equiv) and H₂SO₄ (1 mL) in TFA (5 mL) was stirredfor 2 h at 0° C., and the resulting solution was quenched with 20 mL ofice water, extracted with 3×20 mL of EtOAc, and the organic layerscombined and concentrated under reduced pressure. The residue waspurified by Prep-HPLC eluting with H₂O/CH₃CN to afford 33.7 mg (9.58%)of the title compound as a white solid. LCMS. [M+H]⁺ 524.20. ¹H NMR (300MHz, Methanol-d₄) δ 8.61 (d, J=0.9 Hz, 2H), 8.06 (s, 1H), 4.11-3.74 (m,6H), 3.64 (dq, J=5.8, 3.2, 2.7 Hz, 5H), 3.49 (dd, J=14.5, 3.9 Hz, 1H),3.41-3.27 (m, 1H), 2.80 (t, J=6.4 Hz, 2H), 1.16 (d, J=6.2 Hz, 3H).

Example 616:(S)-5-((1-(Methyl(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)amino)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

Step 1:(S)-2-(4-Methoxybenzyl)-5-((1-(methyl(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)amino)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of(S)-2-(4-methoxybenzyl)-5-((1-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)amino)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one (500 mg, 0.777 mmol, 1 equiv), polyoxymethylene (93.23 mg,3.108 mmol, 4 equiv) and sodium cyanoborohydride (96.33 mg, 1.554 mmol,2 equiv) in MeOH (5 mL) was stirred for 2 h at 60° C., and then theresulting solution was concentrated under reduced pressure and theresidue was purified by Prep-HPLC eluting with H₂O/MeOH to afford 350 mg(68.5%) of title compound as a yellow oil. LCMS: [M+H]⁺ 658.25.

Step 2:(S)-5-((1-(Methyl(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)amino)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of(S)-2-(4-methoxybenzyl)-5-((1-(methyl(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)amino)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one(300 mg, 0.456 mmol, 1 equiv) and H₂SO₄ (1 mL) in TFA (5 mL) was stirredfor 2 h at 0° C., and then the resulting solution was concentrated underreduced pressure. The residue was purified by Prep-HPLC eluting withH₂O/CH₃CN to afford (68.9 mg, 28.1%) of the title compound as a whitesolid. LCMS: [M+H]⁺ 538.25. ¹H NMR (300 MHz, DMSO-d₆) δ 13.14 (s, 1H),8.72 (d, J=0.9 Hz, 2H), 8.28 (s, 1H), 5.11 (s, 1H), 3.81 (d, J=19.2 Hz,4H), 3.51 (t, J=5.4 Hz, 4H), 2.67-2.49 (m, 4H), 2.39 (d, J=7.6 Hz, 2H),2.19 (m, 3H), 1.25 (d, J=6.1 Hz, 3H).

Example 617 Isomer A:5-(((S)-1-((R)-2-Amino-4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-oneand Example 617 Isomer B:5-(((S)-1-((S)-2-Amino-4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

Step 1:(S)-5-((1-Hydroxypropan-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one

A solution of Int-A6 (8 g, 24 mmol, 1 equiv), TEA (2.463 g, 24 mmol, 1equiv), and (S)-2-aminopropan-1-ol (1.829 g, 24 mmol, 1 equiv) in EtOH(60 mL) was stirred for 1 h at 60° C. The solvent was concentrated undervacuum and the residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (1/1) to afford 5.39 g (58.5%) of title compoundas a yellow oil. LCMS: [M+H]⁺ 367.44.

Step 2: Ethyl(S,E)-4-(2-(6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-ylamino)propoxy)but-2-enoate

A solution of(S)-5-(1-hydroxypropan-2-ylamino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one(1.7 g, 4.63 mmol, 1 equiv), Pd₂(allyl)₂Cl₂ (85 mg, 0.23 mmol, 0.05equiv),diisopropyl(2′,4′,6′-triisopropyl-3-methoxy-6-methylbiphenyl-2-yl)phosphine(217 mg, 0.46 mmol, 0.10 equiv), Cs₂CO₃ (4.5 g, 13.81 mmol, 2.99 equiv),and ethyl (E)-4-bromobut-2-enoate (2.7 g, 13.99 mmol, 3.02 equiv) intoluene (30 mL) was stirred for 15 h at 80° C. and maintained with aninert atmosphere of nitrogen. The solids were filtered and the solventwas concentrated under reduced pressure and the residue was applied ontoa silica gel column eluting with EtOAc/petroleum ether (30:70) to afford1.13 g (50.9%) of the title compound as a brown oil. LCMS: [M+H]⁺368.17.

Step 3: Ethyl3-(benzylamino)-4-((S)-2-(6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-ylamino)propoxy)butanoate

A solution of ethyl(S,E)-4-(2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)but-2-enoate(1.11 g, 2.315 mmol, 1 equiv), and phenylmethanamine (1.24 g, 0.012mmol, 5 equiv) in butan-1-ol (30 mL) was stirred for 4 h at 100° C. Thesolvent was concentrated under reduced pressure and the residue wasapplied onto a silica gel column eluting with EtOAc/petroleum ether(61:39) to afford 725 mg (53.4%) of the title compound as a yellowsolid. LCMS: [M+H]⁺ 587.30.

Step 4: Ethyl3-((tert-butoxycarbonyl)amino)-4-((S)-2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)butanoate

A solution of ethyl3-(benzylamino)-4-((S)-2-(6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-ylamino)propoxy)butanoate(594 mg, 1.012 mmol, 1 equiv), Pd/C (76.13 mg, 0.202 mmol, 0.20 equiv),H₂ (gas), and (Boc)₂O (662.86 mg, 3.037 mmol, 3 equiv) in MeOH (30 mL)was stirred for 20 h at RT. The solids were filtered and the solvent wasconcentrated under reduced pressure. The residue was applied onto asilica gel column eluting with EtOAc/petroleum ether (30:70) to afford594 mg (98.3%) of title compound as a yellow solid. LCMS: [M+H]⁺ 597.31.

Step 5:3-((Tert-butoxycarbonyl)amino)-4-((S)-2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)butanoicAcid

A solution of ethyl3-((tert-butoxycarbonyl)amino)-4-((S)-2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)butanoate(550 mg, 0.922 mmol, 1 equiv), LiOH (44.15 mg, 1.843 mmol, 2 equiv), andH₂O (3 mL) in THF (15 mL) was stirred for 6 h at RT. The pH value of thesolution was adjusted to 7 with HCl (10 mmol/L). The resulting mixturewas concentrated under reduced pressure. After concentration, theresidue was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN to afford 170 mg (32.4%) of title compound as a yellow oil.LCMS: [M+H]⁺ 569.27.

Step 6: Tert-butyl(4-oxo-1-((S)-2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butan-2-yl)carbamate

A solution of3-[[(tert-butoxy)carbonyl]amino]-4-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy]butanoicacid (150 mg, 0.264 mmol, 1 equiv), Int-A18 (73.5 mg, 0.317 mmol, 1.20equiv), HATU (120.4 mg, 0.317 mmol, 1.2 equiv), and DIPEA (102.3 mg,0.791 mmol, 3 equiv) in DMF (3 mL) was stirred for 1 h at RT. Afterconcentration under reduced pressure, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN to afford 158 mg(76.5%) of title compound as a yellow oil. LCMS: [M+H]⁺ 783.36.

Step 7:5-(((S)-1-((R)-2-Amino-4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-oneand5-(((S)-1-((S)-2-Amino-4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of tert-butyl(4-oxo-1-((S)-2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butan-2-yl)carbamate(148 mg, 0.189 mmol, 1 equiv), and TFA (2 mL) in DCM (10 mL) was stirredfor 1 h at RT. After concentration by reduced pressure, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN. Theresidue was further purified by Prep-HPLC and Chiral Prep-HPLC(CHIRALPAK ID-3, 3 μm, 0.46×5 cm column, eluting with a gradient of MtBE(0.1% DEA):EtOH=70:30, at a flow rate of 1 mL/min) yielding the titlecompounds as white solids and with the stereochemistry arbitrarilyassigned.

Example 617 Isomer A

(6.4 mg, 6.1%) as a white solid. LCMS: [M+H]⁺ 553.22, ¹H NMR (300 MHz,Methanol-d₄) δ 8.62 (s, 2H), 8.04 (s, 1H), 4.24 (s, 1H), 4.03-3.89 (m,4H), 3.75-3.57 (m, 5H), 3.57-3.37 (m, 4H), 2.62 (dd, J=16.1, 4.2 Hz,1H), 2.44 (dd, J=16.4, 8.1 Hz, 1H), 1.31 (d, J=6.6 Hz, 3H). tR=1.245min.

Example 617 Isomer B

(7.0 mg, 6.7%) as a white solid. LCMS: [M+H]⁺ 553.22, tR=1.639 min.

Example 618:(S)-5-((1-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)thio)-4-(trifluoromethyl)pyridazin-3(2H)-one

Step 1:(R)-3-(2-(Benzyloxy)propoxy)-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propan-1-one

A solution of (R)-2-(benzyloxy)propan-1-ol (1.66 g, 10 mmol, 2 equiv),Int-A21 (1.43 g, 5 mmol, 1 equiv), and NaH (20 mg, 0.1 mmol, 0.1 equiv)in 1-methoxy-2-(2-methoxyethoxy)ethane (2.5 mL) was stirred for 24 h atRT. The reaction was quenched with H₂O (30 mL) and the resultingsolution was extracted with EtOAc (3×50 mL) and the organic layerscombined. The solvent was concentrated under reduced pressure and theresidue was applied onto a silica gel column eluting withEtOAc/petroleum ether (45:65) to afford 2.1 g of title compound as ayellow oil. LCMS: [M+H]⁺ 453.22.

Step 2:(R)-3-(2-Hydroxypropoxy)-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propan-1-one

A solution of BCl₃ in DCM (1M, 8.2 mL) and(R)-3-(2-(benzyloxy)propoxy)-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propan-1-one(1.23 g, 2.718 mmol, 1 equiv) in DCM (10 mL, 157.300 mmol, 57.87 equiv)was stirred for 3 h at −10° C. The reaction was quenched with MeOH (20mL). After concentration under reduced pressure, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN toafford 370 mg (37.6%) of title compound as a white solid. LCMS: [M+H]⁺363.18.

Step 3:(S)-2-(4-Methoxybenzyl)-5-((1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)thio)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of(R)-3-(2-hydroxypropoxy)-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propan-1-one(225 mg, 0.621 mmol, 1 equiv), Int-A29 (294 mg, 0.929 mmol, 1.50 equiv),dibenzyl (E)-diazene-1,2-dicarboxylate (1.07 g, 4.647 mmol, 20%), andtriphenylphosphine (244 mg, 0.930 mmol, 1.50 equiv) in THF (1 mL) andtoluene (5 mL) was stirred for 12 h at RT. After concentration underreduced pressure, the residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford 300 mg (73.1%) of titlecompound as a white solid. LCMS: [M+H]⁺ 661.22.

Step 4:(S)-5-((1-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)thio)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of(S)-2-(4-methoxybenzyl)-5-((1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)thio)-4-(trifluoromethyl)pyridazin-3(2H)-one(530 mg, 0.802 mmol, 1 equiv), and TfOH (1 mL) in TFA (10 mL) wasstirred for 1 h at 0° C. The resulting solution was extracted with EtOAc(3×30 mL) and the organic layers combined and concentrated under reducedpressure. The residue was purified by C18 reverse phase chromatographyeluting with H₂O/CH₃CN followed by further purified by Prep-HPLC(YMC-Actus Triart C18 column) using a water/MeCN to afford the titlecompound (24.7 mg, 5.7%) as a white solid. LCMS: [M+H]⁺ 541.16, ¹H NMR(300 MHz, Methanol-d₄) δ 8.60 (s, 2H), 8.16 (s, 1H), 4.12-4.06 (m, 1H),4.03-3.91 (m, 4H), 3.88-3.62 (m, 7H), 3.57-3.51 (m, 1H), 2.70-2.66 (m,2H), 1.41 (d, J=6.9 Hz, 3H).

Example 619 Isomer A:5-(((S)-1-(3-((S)-2-Methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-oneand Example 619 Isomer B:5-(((S)-1-(3-((R)-2-Methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-oneand

Step 1: Tert-butyl2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate

A solution of tert-butyl 2-methylpiperazine-1-carboxylate (1.5 g, 7.49mmol, 1 equiv), 2-chloro-5-(trifluoromethyl)pyrimidine (1.37 g, 7.50mmol, 1.00 equiv), and K₂CO₃ (2.07 g, 15.0 mmol, 2.00 equiv) in NMP (20mL) was stirred for 16 h at 85° C. The reaction mixture was cooled toRT, followed by addition of water. The resulting solids wereprecipitated and collected by filtration, and then washed with water anddrying under vacuum to afford 2.5 g of title compound as a light yellowsolid. LCMS: [M+H]⁺ 347.

Step 2: 2-(3-Methylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidine

A solution of tert-butyl2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carboxylate(3.34 g, 1 equiv) and HCl in 1,4-dioxane (30 mL) was stirred for 1 h atRT. After concentration under reduced pressure, the residue was purifiedby C18 reverse phase chromatography eluting with H₂O/CH₃CN to afford 687mg (31.8%) of title compound as an orange solid. LCMS: [M+H]⁺ 247.

Step 3:5-(((S)-1-(3-((S)-2-Methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-oneand5-(((S)-1-(3-((R)-2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of Int-A13 (200.4 mg, 0.648 mmol, 1 equiv),2-(3-methylpiperazin-1-yl)-5-(trifluoromethyl)pyrimidine (280 mg, 1.14mmol, 1.20 equiv), DIPEA (250 mg, 1.944 mmol, 3.00 equiv), and HATU (295mg, 1.001 mmol, 1.20 equiv) in DMF was stirred for 1 h at RT. Afterconcentration under reduced pressure, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN, followed by chiralchromatography purification (CHIRALPAK IA-3, 5 μm, 2×25 cm column,eluting with a gradient of Hexanes (0.1% DEA):EtOH gradient, at a flowrate of 20 mL/min) yielding the title compounds as white solids and withthe stereochemistry arbitrarily assigned.

Example 619 Isomer A

29.4 mg, 8.4%; LCMS: [M+H]⁺ 538.29, ¹H NMR (300 MHz, DMSO-d₆) δ 12.45(s, 1H), 8.70 (d, J=0.9 Hz, 2H), 7.90 (s, 1H), 6.27 (s, 1H), 4.8-4.5 (m,3H), 4.4-4.1 (m, 2H), 3.9-3.8 (m, 1H), 3.80-3.6 (m, 2H), 3.35 (s, 2H),3.36-3.00 (d, J=5.7 Hz, 2H), 2.9-2.7 (m, 1H), 2.8-2.6 (m, 2H), 1.2 (s,3H), 1.1-0.97 (d, J=6.8 Hz, 3H).

Example 619 Isomer B

26.7 mg, 7.7%; LCMS: [M+H]⁺ 538.29, ¹H NMR (300 MHz, DMSO-d₆) δ 12.45(s, 1H), 8.70 (d, J=0.9 Hz, 2H), 7.90 (s, 1H), 6.27 (s, 1H), 4.80-4.50(m, 3H), 4.50-4.00 (m, 2H), 3.9-3.8 (m, 1H), 3.80-3.60 (m, 2H), 3.55 (s,2H), 3.30-3.10 (m, 2H), 3.10-2.90 (m, 1H), 2.80-2.60 (m, J=6.4 Hz, 2H),1.20 (s, 3H), 1.1-0.97 (d, J=6.8 Hz, 3H).

Example 620:(S)-4-(Trifluoromethyl)-5-((1-(2-((4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)sulfonyl)ethoxy)propan-2-yl)amino)pyridazin-3(2H)-one

Step 1:(S)-5-((1-Hydroxypropan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of Int-A20 (300 mg, 0.94 mmol, 1 equiv),(S)-2-aminopropan-1-ol (77.8 mg, 1.04 mmol, 1.10 equiv) and TEA (286 mg,2.82 mmol, 3.00 equiv) in EtOH (5 mL) was stirred for 2 h at 60° C. Theresulting solution was diluted with water and extracted with EtOAc. Theorganic layers were combined, dried over anhydrous magnesium sulfate,and filtered. The filtrate was concentrated under reduced pressure toafford 350 mg of title compound as a crude colorless oil. LCMS: [M+H]⁺358.13.

Step 2:(S)-2-(4-Methoxybenzyl)-4-(trifluoromethyl)-5-((1-(2-((4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)sulfonyl)ethoxy)propan-2-yl)amino)pyridazin-3(2H)-one

A solution of(S)-5-((1-hydroxypropan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one(200 mg, 0.56 mmol, 1 equiv), Int-A26 (180.4 mg, 0.56 mmol, 1.00 equiv),and Cs₂CO₃ (359.3 mg, 1.10 mmol, 1.97 equiv) in MeCN (4 mL) was stirredfor 16 h at RT. The solids were filtered and the resulting mixture wasconcentrated under reduced pressure to afford a residue which was elutedonto a silica gel column with EtOAc/petroleum ether (1:1) to afford 120mg (31.6%) of the title compound as a light yellow oil. LCMS: [M+H]⁺680.20.

Step 3:(S)-4-(Trifluoromethyl)-5-((1-(2-((4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)sulfonyl)ethoxy)propan-2-yl)amino)pyridazin-3(2H)-one

A solution of(S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-(2-((4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)sulfonyl)ethoxy)propan-2-yl)amino)pyridazin-3(2H)-one(110 mg, 0.162 mmol, 1 equiv) and TfOH (0.4 mL) in TFA (4 mL) wasstirred for 1 h at RT. After concentration under reduced pressure, theresidue was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN to afford 19.1 mg (21.1%) of the title compound as a whitesolid. LCMS: [M+H]⁺ 560.14. ¹H NMR (400 MHz, DMSO-d₆) δ 12.46 (s, 1H),8.74 (s, 2H), 7.90 (s, 1H), 6.27 (dd, J=8.6, 4.2 Hz, 1H), 4.14 (s, 1H),3.92 (t, J=5.1 Hz, 4H), 3.78 (t, J=6.0 Hz, 2H), 3.53 (m, 2H), 3.35 (d,J=5.9 Hz, 2H), 3.25 (t, J=5.1 Hz, 4H), 1.13 (d, J=6.5 Hz, 3H).

Example 621 Isomer A:(S)-5-((1-((3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)thio)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-oneand Example 621 Isomer B:(R)-5-((1-((3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)thio)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

Step 1: Methyl 3-((2-oxopropyl)thio)propanoate

A solution of 3-mercaptopropanoate (2 g, 16.6 mmol, 1 equiv),1-bromopropan-2-one (2.28 g, 16.6 mmol, 1.00 equiv), and TEA (2.53 g,25.0 mmol, 1.5 equiv) in DCM (20 mL) was stirred for 30 min at RT. Thereaction was then quenched by the addition of 50 mL of water and theresulting solution was extracted with 3×50 mL of DCM, the organic layersdried over anhydrous sodium sulfate, and concentrated under reducedpressure to afford the title compound 2.9 g (98.9%) as a colorless oil.

Step 2: Methyl 3-((2-hydroxypropyl)thio)propanoate

A solution of methyl 3-((2-oxopropyl)thio)propanoate (2.9 g, 16.5 mmol,1 equiv) and NaBH₄ (934 mg, 24.7 mmol, 1.5 equiv) in MeOH (50 mL) wasstirred for 30 min at RT. The reaction was then quenched by the additionof 50 mL of water. The resulting solution was extracted with 3×50 mL ofEtOAc, dried over anhydrous sodium sulfate, and concentrated underreduced pressure to afford the title compound (2.67 g, 91.0%) as acolorless oil.

Step 3: Methyl3-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propyl)thio)propanoate

A solution of Int-A20 (804.5 mg, 2.53 mmol, 0.9 equiv), methyl3-((2-hydroxypropyl)thio)propanoate (500 mg, 2.805 mmol, 1.0 equiv), andsodium metal (168.3 mg, 4.21 mmol, 1.5 equiv) in THF (5 mL) was stirredfor 6 h at RT. The reaction mixture was poured into 20 mL HCl (1 M) andthe resulting solution was extracted with 3×50 mL of EtOAc, the combinedorganic layers were dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was applied onto asilica gel column with EtOAc/petroleum ether (1:1) to afford 850 mg oftitle compound as a white solid. LCMS: [M+H]⁺ 461.31.

Step 4:3-((2-((1-(4-Methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propyl)thio)propanoicAcid

A solution of methyl3-((2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propyl)thio)propanoate(850 mg, 1.85 mmol, 1 equiv), lithium hydroxide (309 mg, 7.36 mmol, 3.99equiv), and H₂O (4 mL) in THF (12 mL) was stirred for 2 h at RT. Thereaction mixture was diluted with H₂O and extracted with DCM. The pHvalue of the water layer was adjusted to 5 with HCl, followed byextraction with 3×30 mL of EtOAc. The organic layers were combined,dried over anhydrous sodium sulfate, and concentrated under reducedpressure to afford 150 mg (18.2%) of the title compound as a yellow oil.LCMS: [M+H]⁺ 447.11.

Step 5:2-(4-Methoxybenzyl)-5-((1-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)thio)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of3-[[2-([1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy)propyl]sulfanyl]propanoicacid (200 mg, 0.448 mmol, 1.0 equiv), Int-A2 (114.4 mg, 0.492 mmol, 1.1equiv), DIPEA (202.5 mg, 1.57 mmol, 3.5 equiv), and HATU (204.5 mg,0.538 mmol, 1.2 equiv) in DMF (3 mL) was stirred for 2 h at RT. Thereaction was then quenched by the addition of 30 mL of water and theresulting solution was extracted with 3×30 mL of EtOAc, organic layersdried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was eluted onto a silica gel column withEtOAc/petroleum ether (2:1) to afford 230 mg of title compound as ayellow oil. LCMS: [M+H]⁺ 661.20.

Step 6:(S)-5-((1-((3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)thio)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-oneand(R)-5-((1-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)thio)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of2-(4-methoxybenzyl)-5-((1-((3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)thio)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one (210 mg, 0.318 mmol, 1.0 equiv), and TfOH (381.6 mg, 2.54 mmol,8.00 equiv) in TFA (3 mL) was stirred for 30 min at RT. The resultingmixture was concentrated under reduced pressure. The reaction mixturewas then quenched by the addition of 20 mL of NH₃ (7 M in MeOH). Afterconcentration under reduced pressure, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN and then separatedby chiral HPLC (CHIRALPAK IC, 5 μm, 2×25 cm column, eluting with agradient of Hexanes (0.1% formic acid):EtOH gradient, at a flow rate of20 mL/min) yielding the title compounds as white solids. The absolutestereochemistry was assigned based on a protein X-ray crystal structureobtained of Example 513A, which confirmed (S)-absolute stereochemistryof the more potent enantiomer.

Example 621 Isomer A

8.6 mg, 10.0%, LCMS: [M+H]⁺ 541.14, ¹H NMR (300 MHz, DMSO-d₆) δ 13.29(s, 1H), 8.74 (d, J=0.9 Hz, 2H), 8.34 (s, 1H), 5.14 (q, J=6.0 Hz, 1H),3.83 (dd, J=17.2, 5.7 Hz, 4H), 3.57 (dd, J=6.6, 4.0 Hz, 4H), 2.95-2.62(m, 6H), 1.38 (d, J=6.0 Hz, 3H).

Example 621 Isomer B

8.9 mg, 10.4%, LCMS: [M+H]⁺ 541.14, ¹H NMR (300 MHz, DMSO-d₆) δ 13.29(s, 1H), 8.74 (d, J=0.9 Hz, 2H), 8.34 (s, 1H), 5.14 (q, J=6.0 Hz, 1H),3.83 (dd, J=17.5, 5.7 Hz, 4H), 3.57 (dd, J=6.6, 3.9 Hz, 4H), 3.04-2.60(m, 6H), 1.38 (d, J=6.0 Hz, 3H).

Example 622:(S)-5-((1-(3-Oxo-3-(4-(5-(trifluoromethyl)thiazol-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

Step 1:(S)-2-(4-Methoxybenzyl)-5-((1-(3-oxo-3-(4-(5-(trifluoromethyl)thiazol-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of(S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoicacid (200 mg, 0.466 mmol, 1 equiv), Int-A27 (140 mg, 0.590 mmol, 1.27equiv), DIPEA (181 mg, 1.400 mmol, 3.01 equiv), and HATU (266 mg, 0.700mmol, 1.50 equiv) in DMF (2 mL) was stirred for 1 h at RT. The crudeproduct was purified by reverse phase column chromatography to afford256 mg (84.7%) of title compound as a yellow oil. LCMS: [M+H]⁺ 648.20.

Step 2:(S)-5-((1-(3-oxo-3-(4-(5-(trifluoromethyl)thiazol-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of(S)-2-(4-methoxybenzyl)-5-((1-(3-oxo-3-(4-(5-(trifluoromethyl)thiazol-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one(240 mg, 0.370 mmol, 1 equiv), and TfOH (0.3 mL) in TFA (3 mL) wasstirred for 1 h at RT. The reaction was then quenched by the addition ofwater and the pH value of the solution was adjusted to 8 withNaHCO₃(aq). The resulting solution was extracted with 3×30 mL of DCMdried over anhydrous sodium sulfate and concentrated under reducedpressure. The crude product was purified by reverse phase columnchromatography and further purification by Prep-HPLC to afford the titlecompound (48.5 mg, 24.8%) as a white solid. LCMS: [M+H]⁺ 529.14. ¹HNMR(300 MHz, DMSO-d₆) δ 12.44 (s, 1H), 7.89 (s, 1H), 7.72 (d, J=1.5 Hz,1H), 6.25 (dd, J=4.2, 3.9 Hz, 1H), 4.16-4.08 (m, 1H), 3.69-3.66 (m, 2H),3.66-3.57 (m, 4H), 3.56-3.45 (m, 6H), 2.57 (d, J=6.4 Hz, 2H), 1.12 (d,J=6.0 Hz, 3H).

Example 623:(S)-5-((1-(3-(4-(5-(Tert-butyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

Step 1: 2-(Tert-butyl)malonaldehyde

A solution of 2-(tert-butyl)malononitrile (3.66 g, 30.0 mmol, 1 equiv)and diisobutylaluminum hydride (60 mL, 90 mmol, 1.5 M) in toluene (70mL) was stirred for 1 h at −60° C. The resulting solution was stirredfor additional 3 h at RT. The reaction was then quenched by the additionof 1M HCl and the pH value of the solution was adjusted to 5 with HCl.The resulting solution was extracted with EtOAc and the organic layerscombined and concentrated under reduced pressure to afford 2 g (52.1%)of the title compound as a white oil. LCMS: [M+H]⁺ 129.10.

Step 2: 5-(Tert-butyl)pyrimidin-2(1H)-one

A solution of urea (1,124.5 mg, 18.7 mmol, 1.2 equiv) and HCl (4 mL, 47mmol, 3 equiv) in EtOH (40 mL) was stirred for 10 min at RT followed byaddition of 2-(tert-butyl)malonaldehyde (2 g, 15.6 mmol, 1 equiv). Thereaction mixture was stirred for 16 h at 75° C. The resulting mixturewas concentrated under reduced pressure to afford 3.5 g of the titlecompound as a crude white solid. LCMS: [M+H]⁺ 153.11.

Step 3: 5-(Tert-butyl)-2-chloropyrimidine

A solution of 5-(tert-butyl)pyrimidin-2(1H)-one (3.5 g, 23.0 mmol, 1equiv) and phosphoryl trichloride (40 mL) was stirred for 5 h at 160° C.The resulting mixture was concentrated under reduced pressure, quenchedby the addition of water, and the pH value of the solution was adjustedto 8 with aqueous NaOH (1M). The resulting solution was extracted withDCM and the organic layers combined and concentrated under reducedpressure to afford 2 g (51.0%) of the title compound as a dark brownsolid. LCMS: [M+H]⁺ 171.08.

Step 4: Tert-butyl4-(5-(tert-butyl)pyrimidin-2-yl)piperazine-1-carboxylate

A solution of 5-(tert-butyl)-2-chloropyrimidine (2 g, 11.7 mmol, 1equiv), tert-butyl piperazine-1-carboxylate (4366.0 mg, 23.4 mmol, 2equiv), and K₂CO₃ (4049.6 mg, 29.3 mmol, 2.5 equiv) in NMP (30 mL) wasstirred for 3 h at 80° C. The resulting solution was extracted withEtOAc and the organic layers combined and concentrated under reducedpressure. The residue was applied onto a silica gel column withEtOAc/petroleum ether (1:10) to afford 1.1 g (29.3%) of title compoundas a solid. LCMS: [M+H]⁺ 321.24.

Step 5: 5-(Tert-butyl)-2-(piperazin-1-yl)pyrimidine

A solution of tert-butyl4-(5-(tert-butyl)pyrimidin-2-yl)piperazine-1-carboxylate (1.1 g, 3.43mmol, 1 equiv) in HCl (gas) in 1,4-dioxane (20 mL) was stirred for 1 hat RT. The resulting mixture was concentrated under reduced pressure andthe residue was dissolved in 10 mL of water. The pH value of thesolution was adjusted to 7 with aqueous NaOH (1 mol/L). Afterconcentration under reduced pressure, the residue was purified by C18reverse phase chromatography eluting with H₂O/CH₃CN to afford 170 mg(22.5%) of title compound as a yellow solid. LCMS: [M+H]⁺ 221.19.

Step 6:(S)-5-((1-(3-(4-(5-(Tert-butyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of 5-(tert-butyl)-2-(piperazin-1-yl)pyrimidine (80 mg, 0.363mmol, 1 equiv),(S)-3-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoicacid (187.10 mg, 0.436 mmol, 1.2 equiv), HATU (165.68 mg, 0.436 mmol,1.2 equiv), and DIPEA (140.79 mg, 1.089 mmol, 3 equiv) in DMF (4 mL) wasstirred for 1 h at RT. The resulting solution was extracted with EtOAcand the organic layers combined. After concentration, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN toafford 210 mg (91.6%) of the title compound as a yellow oil. LCMS:[M+H]⁺ 632.33.

Step 7:(S)-5-((1-(3-(4-(5-(Tert-butyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of(S)-5-((1-(3-(4-(5-(tert-butyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (200 mg, 0.317 mmol, 1 equiv) and TfOH (1 mL) in TFA (10 mL)was stirred for 1 h at RT. The resulting solution was extracted withEtOAc (3×30 mL) and the organic layers combined. After concentration,the residue was purified by C18 reverse phase chromatography elutingwith H₂O/CH₃CN and then the crude product was further purified byPrep-HPLC (YMC-Actus Triart C18, 5 μm, 20×250 mm column, eluting with agradient of water (10 mmol/L NH₄HCO₃)/ACN, at a flow rate of 60 mL/min)to afford the title compound as a white solid (73.5 mg, 45.4%). LCMS:[M+H]⁺ 512.27, ¹H NMR (300 MHz, DMSO-d₆) δ 12.46 (s, 1H), 8.43 (s, 2H),7.91 (s, 1H), 6.28 (dd, J=8.6, 4.3 Hz, 1H), 4.14 (s, 1H), 3.68-3.64 (m,6H), 3.49-3.47 (m, 6H), 2.60-2.56 (m, 2H), 1.26 (s, 9H), 1.14 (d, J=6.5Hz, 3H).

Example 624:(S)-5-((1-Methoxy-3-(2-((4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)sulfonyl)ethoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

Step 1:(R)-5-((1-Hydroxy-3-methoxypropan-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one

A solution of (R)-2-amino-3-methoxypropan-1-ol hydrochloride (300.0 mg,2.12 mmol, 1.00 equiv), Int-A6 (696.6 mg, 2.12 mmol, 1.00 equiv), andTEA (643.2 mg, 6.36 mmol, 3.00 equiv) in EtOH (10.0 mL) was stirred for1 h at 60° C. After concentration under reduced pressure, the residuewas purified by C18 reverse phase chromatography eluting with H₂O/CH₃CNto afford 460 mg (54.6%) of title compound as a yellow oil. LCMS [M+H]+398.18.

Step 2:(S)-5-((1-Methoxy-3-(2-((4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)sulfonyl)ethoxy)propan-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one

A solution of Cs₂CO₃ (288.6 mg, 0.886 mmol, 0.80 equiv),(R)-5-((1-hydroxy-3-methoxypropan-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one(440.0 mg, 1.107 mmol, 1.00 equiv) and Int-A26 (356.8 mg, 1.107 mmol,1.00 equiv) in CH₃CN (10.00 mL) was stirred for 5 h at RT. The solidwere filtered and filtrate concentrated under reduced pressure to afforda residue which was purified by C18 reverse phase chromatography elutingwith H₂O/CH₃CN to yield 450 mg (56.5%) of title compound as a yellowoil. LCMS [M+H]+ 720.26.

Step 3:(S)-5-((1-Methoxy-3-(2-((4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)sulfonyl)ethoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of(S)-5-((1-methoxy-3-(2-((4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)sulfonyl)ethoxy)propan-2-yl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one(430.0 mg, 0.597 mmol, 1.00 equiv) and TFA (2.0 mL) in DCM (10.0 mL) wasstirred for 1 h at RT. The resulting mixture was concentrated underreduced pressure and the pH value of the solution was adjusted to 7 withaqueous NaOH (1 mol/L). After concentration under reduced pressure, theresidue was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN and further purified by Prep-HPLC (Xselect CSH F-Phenyl OBD, 5μm, 19×150 mm column, eluting with a gradient of water (10 mmol/LNH₄HCO₃)/ACN, at a flow rate of 25 mL/min) to afford the title compound(193.8 mg, 55.0%) as a white solid. LCMS [M+H]+ 590.17, ¹H NMR (300 MHz,DMSO-d₆) δ 12.50 (s, 1H), 8.74 (s, 2H), 7.92 (s, 1H), 6.24 (dd, J=8.9,4.4 Hz, 1H), 4.28 (dd, J=3.6, 3.0 Hz, 1H), 3.93-3.90 (m, 4H), 3.80-3.76(m, 2H), 3.59 (d, J=5.7, 2H), 3.44 (dd, J=6.3, 5.4 Hz, 2H), 3.40-3.34(m, 5H). 3.27-3.26 (m, 4H).

Example 625:(S)-4-(Trifluoromethyl)-5-((1-(2-((4-(5-(trifluoromethyl)thiazol-2-yl)piperazin-1-yl)sulfonyl)ethoxy)propan-2-yl)oxy)pyridazin-3(2H)-one

Step 1:(S)-2-(4-((2-(2-(Benzyloxy)propoxy)ethyl)sulfonyl)piperazin-1-yl)-5-(trifluoromethyl)thiazole

A solution of Int A-28 (1.10 g, 3.36 mmol, 1.00 equiv),(S)-2-(benzyloxy)propan-1-ol (0.56 g, 3.36 mmol, 1.00 equiv), and Cs₂CO₃(2.19 g, 6.72 mmol, 2.00 equiv) in CH₃CN (10.0 mL) was stirred for 2 hat RT. The solids were filtered and the resulting solution wasconcentrated under reduced pressure and the resulting residue waspurified by silica gel column chromatography with EtOAc/petroleum ether(27/73) to afford 1.5 g (85.0%) of the title compound as a yellow oil.LCMS [M+H]+ 494.13.

Step 2.(S)-1-(2-((4-(5-(Trifluoromethyl)thiazol-2-yl)piperazin-1-yl)sulfonyl)ethoxy)propan-2-ol

A solution of(S)-2-(4-((2-(2-(benzyloxy)propoxy)ethyl)sulfonyl)piperazin-1-yl)-5-(trifluoromethyl)thiazole(300.0 mg, 0.405 mmol, 1.00 equiv), and BCl₃ (0.50 mL, 1 M, 1.00 equiv)in DCM (5.00 mL) was stirred for 1 h at 0° C. in a water/ice bath. ThepH value of the solution was adjusted to 7 with NaOH/H₂O and then theresulting solution was extracted with 3×20 mL of DCM. The organic layerwas combined and concentrated under reduced pressure to afford 200 mg(97.9%) of title compound as a yellow solid. LCMS [M+H]+ 404.08.

Step 3:(S)-2-(4-Methoxybenzyl)-4-(trifluoromethyl)-5-((1-(2-((4-(5-(trifluoromethyl)thiazol-2-yl)piperazin-1-yl)sulfonyl)ethoxy)propan-2-yl)oxy)pyridazin-3(2H)-one

A solution of(S)-1-(2-((4-(5-(trifluoromethyl)thiazol-2-yl)piperazin-1-yl)sulfonyl)ethoxy)propan-2-ol(140.0 mg, 0.347 mmol, 1.00 equiv), Int-A20 (110.6 mg, 0.347 mmol, 1.00equiv), and t-BuONa (6.67 mg, 0.069 mmol, 0.20 equiv) in DCM (5.0 mL)was stirred for 4 h at 0° C. in a water/ice bath. The reaction was thenquenched by the addition of water and the resulting solution wasextracted with 3×30 mL of EtOAC. After concentration under reducedpressure, the residue was purified by C18 reverse phase chromatographyeluting with H₂O/CH₃CN to afford 80 mg (31.3%) of title compound. LCMS[M+H]+ 686.15.

Step 4: (S)-4-(Trifluoromethyl)-5-((1-(2-((4-(5-(trifluoromethyl)thiazol-2-yl)piperazin-1-yl)sulfonyl)ethoxy)propan-2-yl)oxy)pyridazin-3(2H)-one

A solution of(S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-(2-((4-(5-(trifluoromethyl)thiazol-2-yl)piperazin-1-yl)sulfonyl)ethoxy)propan-2-yl)oxy)pyridazin-3(2H)-one (75.0 mg, 0.109 mmol, 1.00 equiv), and H₂SO₄ (0.75 mL) in TfOH(5.0 mL) was stirred for 30 min at 0° C. in a water/ice bath. Thereaction mixture was then quenched by the addition of water and the pHvalue of the solution was adjusted to 8 with NaOH/H₂O. The resultingsolution was extracted with 3×30 mL of EtOAc. After concentration, theresidue was purified by C18 reverse phase chromatography eluting withH₂O/CH₃CN to afford 27.2 mg (41.8%) of title compound as a white solid.LCMS [M+H]+ 566.00. ¹H NMR (300 MHz, Methanol-d₄) δ 8.21 (s, 1H), 7.58(q, J=1.4 Hz, 1H), 5.11 (td, J=6.8, 2.9 Hz, 1H), 3.96-3.77 (m, 2H),3.76-3.57 (m, 6H), 3.39 (dd, J=6.3, 4.0 Hz, 4H), 3.32-3.21 (m, 2H), 1.34(d, J=6.3 Hz, 3H).

Example 626:5-(((2S)-1-(2-Hydroxy-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

Step 1: Tert-butyl ((2S)-1-(oxiran-2-ylmethoxy)propan-2-yl)carbamate

A solution of 2-(chloromethyl)oxirane (0.52 g, 10.8 mmol, 1.00 equiv),tert-butyl (S)-(1-hydroxypropan-2-yl)carbamate (1 g, 0.011 mmol, 1.00equiv), and NaH (274 mg, 13.0 mmol, 1.2 equiv) in DMF (5.00 mL) wasstirred for 1 h at 0° C. in a water/ice bath. The reaction was quenchedby the addition of water and the resulting solution was extracted with3×30 mL of EtOAc and the organic layers combined and dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford 900 mg (70%) of title compound as a yellow oil. LCMS [M+H]+232.25.

Step 2: Tert-butyl((2S)-1-(2-hydroxy-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)carbamate

A solution of tert-butyl((2S)-1-(oxiran-2-ylmethoxy)propan-2-yl)carbamate (860 mg, 3.70 mmol,1.00 equiv), Int-A3 (860 mg, 3.70 mmol, 1.00 equiv), and DIPEA (1.99 g,0.432 mmol, 5 equiv) in EtOH (10.0 mL) was stirred for 1 h at 60° C. inan oil bath. The resulting solution was applied onto a silica gel columneluting with EtOAc/petroleum ether (50:50) to afford 300 mg of titlecompound as a yellow oil. LCMS [M+H]+ 364.24.

Step 3:1-((S)-2-Aminopropoxy)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propan-2-ol

A solution of tert-butyl((2S)-1-(2-hydroxy-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)carbamate(300.0 mg, 0.647 mmol, 1.00 equiv) and HCl (gas) in 1,4-dioxane (2.00mL) was stirred for 30 min at RT. The resulting mixture was concentratedunder reduced pressure to afford 200 mg (90%) of title compound as awhite solid. LCMS [M+H]+ 364.19.

Step 4:5-(((2S)-1-(2-Hydroxy-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of1-((S)-2-aminopropoxy)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propan-2-ol(256 mg, 0.70 mmol, 1.5 equiv), Int-A20 (150 mg, 0.47 mmol, 1.00 equiv),TEA (95 mg, 0.94 mmol, 2 equiv), and EtOH (5 mL) was stirred for 1 h at40° C. After concentration under reduced pressure of the reactionmixture, the residue was applied onto a silica gel column eluting withEtOAc/petroleum ether (95/5) to afford 200 mg (65.8%) of title compoundas a white solid. LCMS [M+H]+ 646.25.

Step 5:5-(((2S)-1-(2-Hydroxy-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

A solution of5-(((2S)-1-(2-hydroxy-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one (190.0 mg, 0.294 mmol, 1.00 equiv) and H₂SO₄ (0.50 mL) in TfOH(5.00 mL) was stirred for 1 h at −10° C. The reaction mixture wasquenched by the addition of water and was extracted with 3×20 mL ofEtOAc. After concentration under reduced pressure, the residue waspurified by C18 reverse phase chromatography eluting with H₂O/CH₃CN toafford the title compound (29.3 mg, 19%) as a white solid. LCMS [M+H]+526.25. ¹H NMR (300 MHz, DMSO-d₆) δ 12.44 (s, 1H), 8.68 (s, 2H), 7.93(s, 1H), 6.30 (s, 1H), 4.60 (s, 1H), 4.17 (s, 1H), 3.77 (m, 6H),3.5-3.26 (m, 4H), 2.42 (m, 3H), 2.29 (m, 2H), 1.15 (d, J=6.5 Hz, 3H).

Further example compounds of the invention prepared by the methodsdescribed herein are provided in Table E11.

TABLE E11 Example MS No. Structure (M + H)⁺ 627*

  (S)-5-(1-(((3-(4-(5-Chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropyl)amino)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one563.18 628*

  (R)-5-(1-(((3-(4-(5-Chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropyl)amino)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one563.18 629*

 (S)-5-(1-(((3-Oxo-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propyl)amino)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one596.21 630*

 (R)-5-(1-(((3-Oxo-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propyl)amino)methyl)isoindolin-2-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one596.21 631

  (S)-4-Bromo-5-((1-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)oxy)pyridazin-3(2H)-one 501.06 632

 5-(((2R,3R)-3-Hydroxy-1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)butan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 554.19 633

  (S)-5-((1-(3-(4-(5-Chloropyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)-3-hydroxypropan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 505.15634

  (S)-5-((1-(4-Oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one538.19 635

 5-(((2R,3S)-3-Hydroxy-1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)butan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 554.19 636

  (S)-4-Chloro-5-(methyl(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)pyridazin-3(2H)-one 504.17637

  (S)-5-((1-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)-3-(pyridin-3-yl)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 601.20 638^(#)

  6-(4-(2-((2R,5R)-5-(((6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)methyl)pyrrolidin-2-yl)acetyl)piperazin-1-yl)nicotinonitri1e 492.19 639^(#)

  6-(4-(2-((2S,5S)-5-(((6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)methyl)pyrrolidin-2-yl)acetyl)piperazin-1-yl)nicotinonitrile 492.19 640

  (S)-5-((4-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)butan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one538.19 641

  (S)-5-(Methyl(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 538.19 642

  5-((5-(2-Oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)pyrrolidin-2-yl)methoxy)-4-(trifluoromethyl)pyridazin-3(2H)-one 536.18 643

  (S)-5-((4-Hydroxy-1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)butan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 554.19 644

  (S)-5-((1-(3-(4-(5-Chloropyrazin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 490.15 645

 (S)-6-(4-(3-(Methyl(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propyl)amino)propanoyl)piperazin-1-yl)nicotinonitrile 494.20646

  (S)-1′-(3-(2-((6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)propanoyl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-5-carbonitrile 478.16 647

  (S)-5-((1-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)-3-(pyridin-4-yl)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 601.20 648^(#)

  (S)-5-((1-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)-3-(piperidin-4-yl)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 607.25 649^(#)

  (R)-5-((1-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)-3-(piperidin-4-yl)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 607.25 650

  (S)-6-(4-(3-(2-((5-Bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy)propoxy)propanoyl)piperazin-1-yl)nicotinonitrile 491.10 651

  (S)-4-Chloro-5-((1-methoxy-3-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)pyridazin-3(2H)-one 520.16 652

  (S)-5-((1-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 521.17 653^(#)

  (S)-5-((2-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)-1-(piperidin-4-yl)ethyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 593.23 654^(#)

  (R)-5-((2-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)-1-(piperidin-4-yl)ethyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 340.20 655

  (S)-6-(4-(3-(2-((6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)thio)propoxy)propanoyl)piperazin-1-yl)nicotinonitrile 497.15 656

  (S)-2-(6-(4-(3-(2-((6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)propanoyl)piperazin-1-yl)pyridin-3-yl)acetonitrile 495.19657

  (S)-4-Bromo-5-((1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)butan-2-yl)oxy)pyridazin-3(2H)-one 549.10 658

  (S)-6-(1-(3-(2-((6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)propanoyl)piperidin-4-yl)nicotinonitrile 480.18 659

  (S)-4-Bromo-5-((1-hydroxy-3-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)pyridazin-3(2H)-one 537.10 660

  (S)-4-Bromo-S-((1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)oxy)pyridazin-3(2H)-one 550.09 661

  (S)-5-((1-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl-2,2,3,3,5,5,6,6-d8)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 532.23 662

  (S)-5-((1-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrazin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin- 3(2H)-one525.16 663

 (S)-6-(4-(3-(3-Morpholino-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)propanoyl)piperazin-1-yl)nicotinonitrile 566.23 664

  (S)-5-((1-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin- 3(2H)-one523.18 665

  (S)-5-((1-(3-(4-(5-Chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)-3-hydroxypropan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one506.15 666*

 (S)-4-Bromo-5-((1-methoxy-3-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)oxy)pyridazin-3(2H)-one 565.09667*

  (R)-4-Bromo-5-((1-methoxy-3-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)oxy)pyridazin-3(2H)-one 565.09668

  (S)-4-Bromo-5-((1-methoxy-3-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)pyridazin-3(2H)-one 564.11669

  (S)-5-((1-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)-1,4-diazepan-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 538.19 670

  (S)-5-((1-(3-(4-(5-Methylpyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin- 3(2H)-one470.20 671

  (S)-5-((1-(3-(4-(5-Methylpyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin- 3(2H)-one469.21 672

  (R)-5-((1-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 524.18 673

  (S)-5-((1-(3-(4-(5-(Aminomethyl)pyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one485.20 674

  (S)-5-((1-(3-Oxo-3-(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin- 3(2H)-one523.18 675

  (S)-5-((1-(3-Oxo-3-(4-(pyridin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 455.19 676

  (S)-2-(4-(3-(2-((6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazin-1-yl)nicotinonitrile 480.19 677

  (S)-5-((1-(3-Oxo-3-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 523.18 678

  (S)-5-((1-(3-(4-(5-Chloropyrazin-2-yl)piperazin-1-yl)-3-oxopropoxy)-3-methoxypropan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one520.16 679

  (S)-5-((1-(3-(4-(5-Fluoropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin- 3(2H)-one474.18 680

  (S)-2-(4-(3-(2-((6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazin-1-yl)thiazole-5-carbonitrile 486.15 681

  (S)-5-((1-Methoxy-3-(3-oxo-3-(4-(5-(trifluoromethyl)pyrazin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 554.19 682

  (S)-5-((1-(3-(4-(5-Methylpyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin- 3(2H)-one470.19 683

  (S)-5-(4-(3-(2-((6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazin-1-yl)pyrazine-2- carbonitrile481.18 684

  (S)-5-((1-(3-(4-(5-Fluoropyridin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin- 3(2H)-one473.18 685

  (S)-5-((1-(3-Oxo-3-(4-(6-(trifluoromethyl)pyridin-3-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin- 3(2H)-one523.18 686

  (S)-5-((4-Methoxy-1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)butan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 568.20 687

  (S)-5-((1-(3-(4-(5-Methylpyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin- 3(2H)-one471.19 688^(#)

  5-(((S)-1-(3-Oxo-3-((3aR,6aR)-4-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin- 3(2H)-one550.19 689^(#)

  5-(((S)-1-(3-Oxo-3-((3aS,6aS)-4-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 550.19 690

  (S)-5-((1-Methoxy-3-(3-(4-(5-methylpyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one500.22 691^(#)

  (S)-5-((1-Methoxy-3-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)thio)-4-(trifluoromethyl)pyridazin-3(2H)-one 571.15 692^(#)

 (R)-5-((1-Methoxy-3-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)thio)-4-(trifluoromethyl)pyridazin-3(2H)-one571.15 693

  (S)-4-Bromo-5-((1-(3-(4-(5-chloropyrazin-2-yl)piperazin-1-yl)-3-oxopropoxy)-3-methoxypropan-2-yl)amino)pyridazin-3(2H)-one 530.08 694

  (S)-5-((1-(3-(4-(5-Chloropyrazin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one491.14 695

  (S)-5-((1-Methoxy-3-(3-(4-(5-methylpyrazin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one500.22 696*

  (S)-5-((1-(3-(4-(5-Chloropyrazin-2-yl)piperazin-1-yl)-3-oxopropoxy)-3-methoxypropan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one 521.14697*

  (R)-5-((1-(3-(4-(5-Chloropyrazin-2-yl)piperazin-1-yl)-3-oxopropoxy)-3-methoxypropan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one 521.14698^(#)

 5-(((2R,3S)-3-Methoxy-1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)butan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 568.20 699^(#)

 5-(((2R,3R)-3-Methoxy-1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)butan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 568.20 700

  (S)-4-Bromo-5-((1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)thio)pyridazin-3(2H)-one 551.06 701

  (S)-4-Chloro-5-((1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)thio)pyridazin-3(2H)-one 507.11 702*

  (S)-5-((1-((3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)thio)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 540.15 703*

  (R)-5-((1-((3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)thio)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 540.15 704*

 (R)-5-((1-(3-(4-(5-Chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)-4-hydroxybutan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one 521.14705*

 (S)-5-((1-(3-(4-(5-Chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)-4-hydroxybutan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one 521.14 706

  (S)-5-((1-(3-(4-(5-(Difluoromethyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one506.19 707

  (S)-5-((1-(3-(4-(5-(1,1-Difluoroethyl)pyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin- 3(2H)-one520.20 708

  (S)-5-((1-(3-Oxo-3-(4-(5-(trifluoromethyl)thiazol-2-yl)piperazin-1-yl)propoxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one 530.12 709

  (S)-5-((1-(3-Oxo-3-(4-(2-(trifluoromethyl)thiazol-5-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin- 3(2H)-one529.14 710

  5-(((2S)-1-(3-Oxo-3-(3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 524.18 711

  (S)-2-(4-(3-(2-((6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)propanoyl)piperazin-1-yl)thiazole-5-carbonitrile 487.13 712

  (S)-5-((1-Methoxy-3-(3-oxo-3-(4-(5-(trifluoromethyl)thiazol-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 559.15 713

  (S)-2-(4-(3-(3-Methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)piperazin-1-yl)thiazole-5-carbonitrile 516.16 714

  (S)-6-(4-(3-(2-((6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)oxy)propoxy)propanoyl)piperazin-1-yl-2,2,3,3,5,5,6,6-d8)nicotinonitrile 489.22 715

  (S)-5-((1-(3-(4-(5-Chloropyrimidin-2-yl)piperazin-1-yl-2,2,3,3,5,5,6,6-d8)-3-oxopropoxy)propan-2-yl)oxy)-4-(trifluoromethyl)pyridazin-3(2H)-one 499.18 716

  5-(((25)-1-(3-Oxo-3-(3-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)pyrrolidin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 525.16 717

  2-((1-(3-((S)-2-((6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)pyrrolidin-3-yl)amino)thiazole-5-carbonitrile 486.15 718

  2-((1-(3-((S)-2-((6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)pyrrolidin-3-yl)oxy)thiazole-5-carbonitrile487.13 719

  5-(((2S)-1-(3-Oxo-3-(3-((5-(trifluoromethyl)thiazol-2-yl)amino)pyrrolidin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 395.15 720

  5-(((2S)-1-(3-Oxo-3-(3-((5-(trifluoromethyl)thiazol-2-yl)oxy)pyrrolidin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 530.12 721

  (S)-5-((1-(3-(4-(5-Chlorothiazol-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 495.11 722

  (S)-5-((1-(3-Oxo-3-(4-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 530.13 723

  (S)-5-((1-(3-(4-(5-Chlorothiazol-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)oxy)-4-(trifluoromethyl) pyridazin-3(2H)-one496.10 724

  4-(Trifluoromethyl)-5-(2-(2-((4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)sulfonyl)ethoxy)ethoxy)pyridazin-3(2H)-one 547.11725

  (S)-5-((1-(2-((4-(5-(Tert-butyl)pyrimidin-2-yl)piperazin-1-yl)sulfonyl)ethoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one 548.22 726

  (S)-4-(Trifluoromethyl)-5-((1-(2-((4-(5-(trifluoromethyl)thiazol-2-yl)piperazin-1-yl)sulfonyl)ethoxy)propan-2-yl)amino)pyridazin-3(2H)-one 565.20 727

  (S)-4-Bromo-5-((1-(3-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)-3-oxopropoxy)butan-2-yl)oxy)pyridazin-3(2H)-one 515.07 728

  (S)-4-(Trifluoromethyl)-5-((1-(2-((4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)sulfonyl)ethoxy)propan-2-yl)oxy)pyridazin- 3(2H)-one561.13 729

  (S)-4-Chloro-5-((1-(3-oxo-3-(4-(5-(trifluoromethyl)thiazol-2-yl)piperazin-1-yl)propoxy)propan-2-yl)oxy)pyridazin-3(2H)-one 496.10 730

  (S)-4-Bromo-5-((1-(3-oxo-3-(4-(5-(trifluoromethyl)thiazol-2-yl)piperazin-1-yl)propoxy)propan-2-yl)oxy)pyridazin-3(2H)-one 540.10 731

  (S)-4-Chloro-5-((1-(2-((4-(5-(trifluoromethyl)thiazol-2-yl)piperazin-1-yl)sulfonyl)ethoxy)propan-2-yl)amino)pyridazin- 3(2H)-one531.00 732

  (S)-4-Bromo-5-((1-(2-((4-(5-(trifluoromethyl)thiazol-2-yl)piperazin-1-yl)suIfonyl)ethoxy)propan-2-yl)amino)pyridazin- 3(2H)-one575.00 733

  (S)-5-((1-(3-(4-(5-Methylthiazol-2-yl)piperazin-1-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl) pyridazin-3(2H)-one475.20 ^(#)Absolute stereochemistry arbitrarily assigned. *The absolutestereochemistry was assigned based on a protein X-ray crystal structureobtained of Example 18, isomer B which confirmed (S)-absolutestereochemistry and was observed to be the more potent enantiomer.

Example A. Enzymatic Assay for Inhibition of PARP7

Displacement of Probe A, a biotinylated probe binding to the TIPARPactive site, was measured using a time-resolved fluorescence energytransfer (TR-FRET) assay. 20 nL of a dose response curve of each testcompound was spotted in black 384-well polystyrene proxiplates (PerkinElmer) using a Mosquito (TTP Labtech). Reactions were performed in a 8μL volume by adding 6 JAL of TIPARP and Probe A in assay buffer (20 mMHEPES pH=8, 100 mM NaCl, 0.1% bovine serum albumin, 2 mM DTT and 0.002%Tween20), incubating with test compound at 25° C. for 30 min, thenadding 2 μL of ULight-anti 6×His and LANCE Eu-W1024 labeled streptavidin(Perkin Elmer). The final concentrations of TIPARP and Probe A were 6 nMand 2 nM, respectively. The final concentration of ULight-anti 6×His andLANCE Eu-W1024 labeled streptavidin were 4 nM and 0.25 nM, respectively.Reactions were incubated at 25° C. for an additional 30 min, then readon an Envision plate reader equipped with a LANCE/DELFIA top mirror(Perkin Elmer) using excitation of 320 nm and emission of 615 nm and 665nM with a 90 ρs delay. The ratio of the 665/615 nm emission werecalculated for each well to determine the amount of complex of TIPARPand Probe A in each well. Control wells containing a negative control of0.25% DMSO vehicle or a positive control of 100 μM Example 190 were usedto calculate the % inhibition as described below:

${\% \mspace{14mu} {inhibition}} = {100 \times \frac{{TRF}_{cmpd} - {TRF}_{\min}}{{TRF}_{\max} - {TRF}_{\min}}}$

where TRF_(cmpd) is the TR-FRET ratio from the compound treated well,TRF_(min) is the TR-FRET ratio from the Example 190-treated positivecontrol well and TRF_(max) is the TR-FRET ratio from the DMSO-treatednegative control well.

The % inhibition values were plotted as a function of compoundconcentration and the following 4-parameter fit was applied to derivethe IC₅₀ values:

$Y = {{Bottom} + \frac{\left( {{Top} - {Bottom}} \right)}{\left( {1 + \left( \frac{X}{{IC}_{50}} \right)^{{Hill}\mspace{14mu} {Coefficient}}} \right.}}$

where top and bottom are normally allowed to float, but may be fixed at100 or 0 respectively in a 3-parameter fit. The Hill Coefficient isnormally allowed to float but may also be fixed at 1 in a 3-parameterfit. Y is the % inhibition and X is the compound concentration.

Synthesis of Probe A

Step 1:5-(5-Hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(2.8 g, 8.52 mmol, 1.00 equiv), 2,3-dihydro-1H-isoindol-5-olhydrobromide (4.27 g, 19.76 mmol, 1.00 equiv), and TEA (10 mL) inethanol (40 mL) was stirred for 1 h at 60° C. The resulting solution wasextracted with 2×100 mL of ethyl acetate and the organic layers combinedand concentrated under reduced pressure to afford 4.5 g of the titlecompound as a yellow oil. LCMS: [M+H]⁺ 428.23.

Step 2: tert-Butyl4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate

A solution of5-(5-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(4.5 g, 10.53 mmol, 1.00 equiv), tert-butyl4-iodopiperidine-1-carboxylate (20 g, 64.28 mmol, 8.00 equiv), potassiumcarbonate (15 g, 108.53 mmol, 10.00 equiv), and DMF (50 mL) was stirredfor 2 days at 80° C. The resulting solution was extracted with 2×200 mLof ethyl acetate and the organic layers combined and concentrated underreduced pressure. The residue was applied onto a silica gel columneluting with ethyl acetate/petroleum ether to afford the title compound(2 g, 31%) as a yellow oil. LCMS: [M+H]⁺ 611.15.

Step 3:5-[5-(Piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

A solution of tert-butyl4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate(2 g, 3.27 mmol, 1.00 equiv), dioxane/HCl (5 mL), and dioxane (45 mL)was stirred for 6 h at 25° C. The resulting mixture was concentratedunder reduced pressure. The residue was applied onto a silica gel columnand eluted with ethyl acetate/petroleum ether to afford 1 g of titlecompound as a yellow oil. LCMS: [M+H]⁺ 511.28.

Step 4: tert-Butyl2-[4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidin-1-yl]acetate

A solution of5-[5-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one(1 g, 1.96 mmol, 1.00 equiv), tert-butyl 2-chloroacetate (450 mg, 2.99mmol, 3.00 equiv), DIPEA (5 mL), and dichloromethane (10 mL) was stirredovernight at 25° C. The residue was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford the title compound (540mg, 44%) as a yellow oil. LCMS: [M+H]⁺ 625.20.

Step 5:2-[4-([2-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidin-1-yl]hydrochloride

A solution of tert-butyl2-[4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidin-1-yl]acetate(540 mg, 0.86 mmol, 1.00 equiv) and dioxane/HCl (8 mL) was stirredovernight at 25° C. The resulting mixture was concentrated under reducedpressure. The residue was purified by C18 reverse phase chromatographyeluting with H₂O/CH₃CN to afford 200 mg (53%) of title compound as awhite solid. LCMS: [M+H]⁺ 439.31.

Step 6: Tert-butylN-(6-[5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazolidin-4-yl]pentanamido]hexyl)carbamate

A solution of5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazolidin-4-yl]pentanoicacid (reagent was purchased from Beijing Dragon Rui Trading Company, 976mg, 3.99 mmol, 1.00 equiv), DIPEA (1.55 g, 11.99 mmol, 3.00 equiv), HATU(1.82 g, 4.79 mmol, 1.20 equiv), tert-butyl N-(6-aminohexyl)carbamate(864 mg, 3.99 mmol, 1.00 equiv) in DMF (15 mL) was stirred overnight at25° C. The reaction was then quenched by the addition of 50 mL of water.The solids were collected by filtration to afford 1.5 g (85%) of thetitle compound as a white solid. LCMS: [M+H]⁺ 443.26.

Step 7:5-[(3aS,4S,6aR)-2-Oxo-hexahydro-1H-thieno[3,4-d]imidazolidin-4-yl]-N-(6-aminohexyl)pentanamideHydrochloride

A solution of tert-butylN-(6-[5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazolidin-4-yl]pentanamido]hexyl)carbamate(800 mg, 1.81 mmol, 1.00 equiv) in hydrogen chloride/dioxane (20 mL) wasstirred overnight at 25° C. The resulting mixture was concentrated underreduced pressure to afford 600 mg (88%) of the title compound as a graycrude oil. LCMS: [M+H]⁺ 343.21.

Step 8:5-[(3aS,4S,6aR)-2-Oxo-hexahydro-1H-thieno[3,4-d]imidazolidin-4-yl]-N-(6-[2-[4-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidin-1-yl]acetamido]hexyl)pentanamide

A solution of2-[4-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidin-1-yl]hydrochloride(175 mg, 0.40 mmol, 1.00 equiv), DIPEA (258 mg, 2.00 mmol, 5.00 equiv),HATU (228 mg, 0.60 mmol, 1.50 equiv), 5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazolidin-4-yl]-N-(6-aminohexyl)pentanamidehydrochloride (228 mg, 0.60 mmol, 1.50 equiv) in DMF (3 mL) was stirredfor 4 h at 25° C. The crude product was purified by C18 reverse phasechromatography eluting with H₂O/CH₃CN to afford the title compound as awhite solid (118.3 mg, 39%). LCMS: [M+H]⁺ 763.35.

¹H NMR (DMSO-d₆, 400 MHz) δ: 12.52 (s, 1H), 7.98 (s, 1H), 7.81-7.68 (m,2H), 7.26 (d, J=8.4 Hz, 1H), 7.00 (d, J=2.2 Hz, 1H), 6.91 (dd, J=8.4,2.3 Hz, 1H), 6.45-6.39 (m, 1H), 6.36 (s, 1H), 4.91 (d, J=6.1 Hz, 4H),4.45 (m, 1H), 4.26 (m, 1H), 4.17-4.08 (m, 1H), 3.14-2.96 (m, 5H), 2.91(s, 2H), 2.82 (dd, J=12.4, 5.1 Hz, 1H), 2.73-2.63 (m, 2H), 2.58 (d,J=12.4 Hz, 1H), 2.33 (ddd, J=11.8, 9.4, 3.1 Hz, 2H), 2.11-1.90 (m, 4H),1.76-1.54 (m, 3H), 1.57-1.20 (m, 13H).

IC₅₀ data for the Example compounds is provided below in Table A-1 (“+”is <0.1 μM; “++” is ≥0.1 μM<1 μM; and “+++” is ≥1 μM).

TABLE A-1 IC₅₀ Data for Example Compounds Example No. IC₅₀  1 +  2 + 3 +  4 +  5 ++  6 ++  7 ++  8 ++  9 ++  10 ++  11 +  12 ++  13 +  14 + 15 +  16 ++  17 +  18A ++  18B +  19 +  20 +  21 +  22 +  23 +  24 + 25 +  26 +  27 ++  28 +  29 +  30A +++  30B +  31 +++  32 +  33 +  34 + 35A +++  35B ++  36A +++  36B +  37 +  38A +  38B +  39 +  40 ++  41 + 42 +  43 +  44 +  45 +  46 +  47 +  48 +  49 +  50 +  51 +  52 +  53 + 54 +  55 +  56A +  56B ++  57A ++  57B +  57C ++  57D ++  58 +  59 + 60 ++  61 +  62 +  63 +  64A +++  64B +  65 +  66 +  67 +  68 +  69 + 70 +  71 ++  72A +  72B +  73 +  74 +  75 +  76 +  77 +  78 +  79A + 79B +  79C +  79D +  80A ++  80B ++  81A ++  81B +++  82A +  82B ++  83++  84 ++  85 +  86 ++  87 +  88 +  89 +  90 +  91 ++  92 +  93A +  93B++  94A +  94B +  95A +  95B +  96A +  96B +  97 +  98 +  99 ++ 100A +100B + 101 + 102 + 103 ++ 104 +++ 105 ++ 106 + 107 + 108 ++ 109 ++ 110 +111 ++ 112A ++ 112B +++ 113 + 114 +++ 115 + 116 + 117 ++ 118 + 119 + 120+++ 121A + 121B + 122 + 123A + 123B + 124 + 125 + 126 + 127 + 128A +128B + 129A ++ 129B + 130 ++ 131 ++ 132 ++ 133 + 134 +++ 135 + 136 +137A + 137B + 138 +++ 139 + 140A + 140B ++ 141A + 141B + 141C ++ 141D ++142 +++ 143 +++ 144A + 144B ++ 145A + 145B + 146A + 146B + 147A + 147B +147C ++ 147D + 148A + 148B ++ 148C + 148D + 149A + 149B + 149C + 149D +150 + 151 ++ 152 ++ 153 ++ 154 ++ 155 ++ 156 ++ 157 ++ 158 ++ 159 +++160 + 161 ++ 162 ++ 163 +++ 164 + 165 +++ 166 +++ 167 ++ 168 ++ 169 +170 + 171 +++ 172 ++ 173 ++ 174 + 175 +++ 176 +++ 177 + 178 + 179 ++180 + 181 + 182 +++ 183 +++ 184 +++ 185 +++ 186 +++ 187 +++ 188 ++ 189++ 190 + 191 +++ 192 + 193 + 194 + 195 + 196 + 197 + 198 + 199 + 200 +201 + 202 + 203 + 204 ++ 205 + 206 + 207 +++ 208 +++ 209 + 210 ++ 211 +212 ++ 213 ++ 214 + 215 + 216 + 217 ++ 218 + 219 + 220 ++ 221 +++ 222 +223 + 224 + 225 + 226 + 227 + 228 + 229 + 230 ++ 231 +++ 232 + 233 +234 + 235 +++ 236 + 237 + 238 + 239 +++ 240 ++ 241 ++ 242 ++ 243 +++ 244++ 245 + 246 +++ 247 +++ 248 +++ 249 ++ 250 ++ 251 +++ 252 + 253 ++ 254++ 255 +++ 256 +++ 257 +++ 258 +++ 259 +++ 260 + 261 ++ 262 +++ 263 +264 +++ 265 + 266 + 267 + 268 + 269 + 270 + 271 + 272 +++ 273 + 274 +275 +++ 276 +++ 277 ++ 278 ++ 279 + 280 ++ 281 ++ 282 ++ 283 ++ 284 +285 + 286 + 287 +++ 288 + 289 + 290 ++ 291 ++ 292 +++ 293 +++ 294 + 295++ 296 ++ 297 ++ 298 + 299 + 300 ++ 301 ++ 302 ++ 303 + 304 + 305 +306 + 307 ++ 308 ++ 309 ++ 310 +++ 311 ++ 312 ++ 313 + 314 ++ 315 ++ 316++ 317 ++ 318 ++ 319 ++ 320 + 321 + 322 ++ 323 + 324 ++ 325 ++ 326 + 327++ 328 + 329 + 330 +++ 331 + 332 ++ 333 + 334 ++ 335 ++ 336 + 337 +338 + 339 + 340 + 341 + 342 +++ 343 +++ 344 ++ 345 +++ 346 + 347 + 348 +349 + 350 ++ 351 ++ 352 + 353 + 354 ++ 355 + 356 ++ 357 + 358 + 359 +360 +++ 361 + 362 ++ 363 +++ 364 +++ 365 + 366 + 367 + 368 + 369 ++370 + 371 ++ 372 +++ 373 + 374 + 375 + 376 + 377 + 378 + 379 + 380 +381 + 382 + 383 + 384 + 385 ++ 386 + 387 +++ 388 + 389 ++ 390 + 391 +++392 + 393 ++ 394 + 395 + 396 +++ 397 + 398 + 399 ++ 400 + 401 + 402 +403 + 404 ++ 405 + 406 +++ 407 + 408 + 409 ++ 410 + 411 + 412 + 413 +414 ++ 415 + 416 ++ 417 ++ 418 +++ 419 + 420 +++ 421 ++ 422 +++ 423 +424 +++ 425 +++ 426 + 427 + 428 ++ 429 + 430 ++ 431 + 432 ++ 433 + 434+++ 435 + 436 ++ 437 + 438 +++ 439 + 440 + 441 + 442 + 443 + 444 + 445 +446 + 447 + 448 ++ 449 ++ 450 + 451 ++ 452 + 453 + 454 + 455 + 456 +457 + 458 + 459 ++ 460 + 461 + 462 + 463 + 464 +++ 465 + 466 + 467 +468 + 469 + 470 + 471 + 472 +++ 473 + 474 + 475 + 476 ++ 477 + 478 ++479 ++ 480 + 481 + 482 + 483 + 484 + 485 + 486 + 487 ++ 488 + 489 +++490 + 491 + 492 + 493 + 494 + 495 + 496 + 497 +++ 498 +++ 499 + 500 +501 + 502 +++ 503 + 504 + 505 + 506 + 507 + 508 + 509 + 510 + 511 +512 + 513A + 513B ++ 514A +++ 514B + 515A +++ 515B + 516 + 517 + 518A+++ 518B + 519 + 520 + 521 + 522 + 523 + 524 ++ 525 + 526 ++ 527A + 527B+++ 528A + 528B + 529 + 530A + 530B ++ 530C ++ 530D + 531 + 532A + 532B++ 533 + 534 + 535 + 536 + 537A +++ 537B + 538A ++ 538B + 539A + 539B ++539C + 539D ++ 540 ++ 541 + 542 + 543A + 543B + 543C + 543D ++ 544A +544B ++ 544C + 544D ++ 545A ++ 545B ++ 545C + 545D + 546A + 546B +546C + 546D + 547 + 548 + 549 + 550 + 551 + 552 + 553 + 554 + 555 + 556++ 557 + 558 + 559 + 560A + 560B ++ 560C + 560D ++ 561 + 562 + 563 +564 + 565A ++ 565B ++ 565C + 565D + 566A +++ 566B +++ 566C ++ 566D +++567A + 567B + 567C + 567D + 568A + 568B + 568C + 568D + 569 ++ 570A +570B ++ 571A + 571B ++ 571C +++ 571D ++ 572A + 572B ++ 573A + 573B +573C + 573D + 574A ++ 574B ++ 574C + 574D + 575A +++ 575B +++ 575C ++575D +++ 576A + 576B + 577A + 577B + 578A + 578B + 579 + 580A ++ 580B ++580C + 580D + 581A + 581B + 581C + 581D + 582A +++ 582B ++ 582C +++ 582D+++ 583A + 583B +++ 584 + 585 + 586 + 587 + 588 + 589 + 590 + 591A +591B + 592 + 593 + 594 + 595 + 596 + 597 + 598 + 599 + 600 + 601 + 602 +603 + 604 + 605 + 606 + 607 + 608 + 609 + 610 + 611 + 612A + 612B + 612C+++ 612D +++ 613 + 614A +++ 614B + 614C + 614D + 615 ++ 616 + 617A +617B + 618 + 619A + 619B + 620 + 621A ++ 621B + 622 + 623 + 624 + 625 +626 + 627 + 628 +++ 629 + 630 +++ 631 + 632 + 633 + 634 + 635 + 636 ++637 + 638 ++ 639 +++ 640 + 641 ++ 642 ++ 643 + 644 + 645 + 646 + 647 +648 +++ 649 + 650 + 651 + 652 + 653 +++ 654 + 655 + 656 + 657 + 658 +659 + 660 + 661 + 662 + 663 + 664 + 665 + 666 + 667 +++ 668 + 669 +670 + 671 + 672 ++ 673 + 674 + 675 + 676 + 677 + 678 + 679 + 680 + 681 +682 + 683 + 684 + 685 + 686 + 687 + 688 + 689 ++ 690 + 691 + 692 ++693 + 694 695 + 696 + 697 ++ 698 + 699 + 700 + 701 + 702 + 703 ++ 704 +705 ++ 706 + 707 + 708 + 709 + 710 ++ 711 + 712 + 713 + 714 + 715 +716 + 717 + 718 + 719 + 720 + 721 + 722 + 723 + 724 + 725 + 726 + 727 +728 + 729 ++ 730 ++ 731 + 732 + 733 +

Example B: PARP7 amplification in various cancer types

FIG. 1 illustrates that PARP7 amplification occurs in cancer with thehighest frequency in lung, esophagus, ovarian, cervical and head andneck (upper aerodigestive). FIG. 1A shows PARP7 amplification acrossTCGA primary tumor samples. The results here are in whole or part basedupon publicly available data generated by the TCGA Research Network:https://www.cancer.gov/tcga. The Cancer Genome Atlas program collected,characterized, and analyzed cancer samples from over 11,000 primarycancer and matched normal samples spanning 33 cancer types. The PARP7gene is located on chromosome 3 (3q25) in a region that is frequentlyamplified in cancers of squamous histology (Gao et al. 2013, Cerami etal. 2012). See also: Gao et al., Integrative analysis of complex cancergenomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1(2013); and Cerami et al., The cBio Cancer Genomics Portal: An OpenPlatform for Exploring Multidimensional Cancer Genomics Data. CancerDiscov 2, 401-4 (2012).

FIG. 1B shows PARP7 copy-number amplifications correspond to increasedlevels of PARP7 mRNA expression levels in TCGA lung squamous tumorsamples. Patient samples included 198 samples with diploid, 234amplification gain >1 and 92 with amplification gain >2.

Example C: Inhibition of Cancer Cell Growth by Treatment with PARP7Inhibitors

FIG. 2 illustrates a dose-dependent decrease in growth of NCI-H1373 lungcancer cells. Table A-2 and Table A-3 (below) represents theconcentration that causes 50% growth inhibition (GI₅₀) in a panel ofcancer cell lines with Compound 18B and Compound 561. Cells were platedinto 384-well plates at a pre-specified density in fetal bovineserum-containing media. Cells were treated with compound or vehicle(DMSO) 24 hrs later, and a day zero plate was collected for analysis.Test compound plates were incubated continuously for 72 hrs (Table A-2)or 144 hours (Table A-3) cell growth was assessed using a luminescentcell viability assay (CellTiter-Glo, Promega). The GI₅₀ was determinedby correcting for the cell count at time zero (time of treatment) andplotting data as percent growth relative to vehicle-treated cells.

GI₅₀ data for the Example compound is provided below in Table A-2 (“+”is <0.1 μM; “++” is ≥0.1 μM and <1 μM; and “+++” is ≥1 μM).

TABLE A-2 Growth Inhibition in Different Cancer Cell Lines Compound 18BCell Line Primary Site Histological Subtype GI₅₀ JHOS-2 ovaryadenocarcinoma + NCI-H1373 lung adenocarcinoma + SCC-25 upper squamouscell + aerodigestive carcinoma tract TE-8 oesophagus squamous cell +carcinoma NCI-H2347 lung adenocarcinoma + TYK-nu ovaryundifferentiated + carcinoma COLO-680N oesophagus squamous cell +carcinoma NCI-H1437 lung adenocarcinoma + T3M-10 lung large cellcarcinoma + HCC1937 breast ductal carcinoma + EFE-184 endometrium notspecified + Panc 03.27 pancreas ductal carcinoma + CAL 27 upper squamouscell + aerodigestive carcinoma tract EBC-1 squamous cell carcinoma +lung YD-10B upper squamous cell + aerodigestive carcinoma tract YH-13central nervous astrocytoma Grade IV + system NCI-H596 lung mixedadenosquamous + carcinoma NCI-H1963 lung small cell carcinoma +TUHR1OTKB kidney not specified + NCI-H647 lung mixed adenosquamous +carcinoma GSU stomach adenocarcinoma + IA-LM lung large cell carcinoma +MDA-MB-468 breast not specified + SW 900 lung squamous cell + carcinomaNCI-H1930 lung small cell carcinoma + Caki-1 kidney clear cell renalcell + carcinoma HCC1599 breast ductal carcinoma ++ HCC-2279 lungadenocarcinoma ++ DCF-289 lung adenocarcinoma ++ OVISE ovary clear cellcarcinoma ++ Hs 578T breast ductal carcinoma ++ HCC1187 breast ductalcarcinoma ++ COR-L105 lung adenocarcinoma ++ NCI-H2066 lung small cellcarcinoma ++ HCC827 lung adenocarcinoma ++ SK-BR-3 breast not specified++ HCC-1195 lung mixed adenosquamous ++ carcinoma CFPAC-1 pancreasductal carcinoma ++ NCI-H1975 lung non small cell ++ carcinoma HDQ-P1breast ductal carcinoma ++ NCI-H2081 lung not specified ++ KMBC-2urinary tract not specified ++ NCI-H2228 lung adenocarcinoma ++ L5123large intestine adenocarcinoma ++ KMRC-3 kidney clear cell renal cell ++carcinoma LUDLU-1 lung squamous cell ++ carcinoma SNU-719 stomach notspecified ++ SW620 large intestine adenocarcinoma ++ EN endometrium notspecified ++ GSS stomach adenocarcinoma ++ FaDu upper squamous cell ++aerodigestive carcinoma tract NCI-H441 lung adenocarcinoma ++ NT: NotTested.

TABLE A-3 Growth Inhibition in Different Cancer Cell Lines with Compound561. Compound 561 Cell Line Cancer Type GI₅₀ TYK-nu high grade ovarianserious + adenocarcinoma Caki-1 clear cell renal cell carcinoma + SCC-25tongue squamous cell carcinoma + GCT undifferentiated pleiomorphic +sarcoma NCI-H647 lung adenosquamous carcinoma + NCI-H1373 lungadenocarcinoma + EBC-1 squamous cell lung carcinoma + NCI-H2347 lungadenocarcinoma + Panc 03.27 pancreatic adenocarcinoma + HCC827 lungadenocarcinoma + TUHR1OTKB renal cell carcinoma + IA-LM large cell lungcarcinoma + CFPAC-1 pancreatic ductal ++ adenocarcinoma COR-L105 lungadenocarcinoma ++ SW900 squamous cell lung carcinoma ++ NCI-H2066squamous cell lung carcinoma +++ TE-11 esophageal squamous cell +++carcinoma MSTO-211H biphasic mesothelioma +++ NCI-H2009 lungadenocarcinoma +++ SK-LU-1 lung adenocarcinoma +++ NCI-H2087 lungadenocarcinoma +++ NCI-H1930 small cell lung carcinoma +++ H4neuroglioma +++ LN-18 glioblastoma +++ CAL-27 tongue squamous cellcarcinoma +++ A101D melanoma +++ ACC-MESO-1 mesothelioma +++ AGS gastricadenocarcinoma +++ COLO 680N esophageal squamous cell +++ carcinomaHCC1954 ductal breast carcinoma +++ HPAF-II pancreatic adenocarcinoma+++ HT-1080 fibrosarcoma +++ KAL S-1 glioblastoma +++ KMBC-2 bladdercarcinoma +++ KMRC-3 clear cell renal carcinoma +++ MCAS ovarianmucinous +++ cy stadenocarcinoma MDA-MIB-468 breast adenocarcinoma +++NCI-H1437 lung adenocarcinoma +++ NCI-H1648 lung adenocarcinoma +++NCI-H1944 lung adenocarcinoma +++ NCI-H1963 small cell lung carcinoma+++ NCI-H2291 lung adenocarcinoma +++ NCI-H2444 non-small cell lungcarcinoma +++ NCI-H441 papillary adenocarcinoma of the +++ lung NUGC-3gastric adenocarcinoma +++ SCaBER bladder squamous cell carcinoma +++SF126 glioblastoma multiforme +++ SK-MEL-2 malignant melanoma +++SK-MES-1 squamous cell lung carcinoma +++ SNU-840 malignant ovarianBrenner tumor +++ T84 colon adenocarcinoma +++ YD-10B tongue squamouscell carcinoma +++

Example D: Induction of Interferon Beta-Levels by Treatment with PARP7Inhibitors

FIG. 3 illustrates the induction of interferon-beta (IFN-β) levels byPARP7 inhibitors in CT26 mouse colon cancer cells and RAW264.7 mousemacrophages in the presence of a STING agonist, DMXAA. CT26 cells wereplated in a 96-well plate and allowed to adhere overnight. Cells wereco-treated with a dose-titration of PARP7 inhibitor and 50 μg/mL DMXAAfor 24 hours and supernatants were harvested and immediately processedby ELISA (Invivogen, luex-mifnb) according to kit instructions. Assaylimit of detection defined by 2x the lowest concentration of thestandard curve (LOD=16 pg/mL). IFN-β concentrations interpolated fromthe standard curve and non-linear regression analysis was performedusing a 4-parameter (variable slope) fit in GraphPad Prism.

Example E: Induction of STAT1 Phosphorylation by Treatment with PARP7Inhibitors

FIG. 4 illustrates the induction of STAT1 phosphorylation by a PARP7inhibitor in CT26 mouse colon cancer cells and RAW264.7 mousemacrophages. CT26 cells were plated in 6-well dishes and allowed toadhere overnight. Cells were treated with PARP7 inhibitor (5 μM topdose, 1:3 serial dilution) or interferon-beta (10 ng/mL) for 24 hoursprior to harvest by scraping on ice in RIPA lysis buffer (Millipore,20-188) with HALT protease and phosphatase inhibitor (Thermo, 78444).Lysates (30 μg) were subjected to western immunoblotting using primaryantibodies diluted 1:1000 (Cell Signaling Technologies, 9167, 9172, and5174). After washing with TBST, blots were incubated with secondaryantibody (Licor, 926-32211) diluted at 1:15,000 in blocking buffer andsubsequently scanned using a Licor Odyssey CLx Imager.

Example F: Proliferation of CT26 Cells in the Presence of PARP7Inhibitors

FIG. 5 illustrates that PARP7 inhibitors do not inhibit proliferation inCT26 cells in vitro. CT26 cells were plated in a 384-well plate andallowed to adhere for several hours before being treated with Compound18B. Cells were incubated with compound for 4 days prior to processingwith CellTiter-Glo reagent (Promega). Luminescence was measured with aPerkin Elmer Envision and percent inhibition was calculated using thevehicle (DMSO) average as 0% inhibition. Non-linear regression analysiswas performed using a 4 parameter (variable slope) fit in GraphPadPrism.

Example G: Inhibition of Tumor Growth by Treatment with PARP7 Inhibitors

FIG. 6 illustrates that PARP7 inhibitors significantly reduce tumorgrowth in murine syngeneic models (FIGS. 6A, 6B, and 6C) CT26 and (FIGS.6D, 6E, and 6F) 4T1. For the CT26 study BALB/c mice were inoculatedsubcutaneously at the right flank with CT26 cells for tumor development.Four days after tumor inoculation, 36 mice with tumor size ranging from40-55 mm³ (average tumor size 47 mm³) were selected and assigned into 3groups using stratified randomization with 12 mice in each group basedupon their tumor volumes. The treatments were started from the next daypost randomization (defined randomization day as day 0) and were treatedwith vehicle (0.5% methylcellulose+0.2% Tween 80), Compound 98 (500mg/kg S.C. QD*21 days), Compound 93A (100 mg/kg S.C. BID*21 days)respectively. The tumor sizes were measured three times per week duringthe treatment. The entire study was terminated on day 21.

For the 4T1 study female BALB/c mice were inoculated orthotopically inthe mammary fat pad with 4T1-luc2-1A4 cells for tumor development. Eightdays after tumor inoculation, 45 mice with tumor size ranging from 63-88mm³ (average tumor size 67 mm³) were selected and assigned into 3 groupsusing stratified randomization with 15 mice in each group based upontheir tumor volumes. The treatments were started from the next day postrandomization (defined randomization day as D0) and were treated withvehicle (0.5% methylcellulose+0.2% Tween 80), Compound 98 (500 mg/kgS.C. QD*21 days), Compound 93A (100 mg/kg S.C. BID*21 days)respectively. The tumor sizes were measured three times per week duringthe treatment. The entire study was terminated on D20.

Mean tumor volume and SEM for both studies are plotted. Statisticalsignificance, calculated using two-tailed unpaired t-tests in which eachtreatment group was compared to vehicle control, is indicated by anasterisk. Statistics were performed on groups with less than 20% animalloss (D21 for CT26, D17 for 4T1).

Example H: Inhibition of Tumor Growth by Oral Dosing with a PARP7Inhibitor

The effect of Compound 561 on tumor growth was studied in a humanNCI-H1373 lung cancer xenograft and a murine CT26 colon cancer syngeneicmodel.

For the NCI-H1373 study, SCID mice were inoculated subcutaneously in theright flank with NCI-H1373 cells for tumor development. After 5 days oftumor growth, mice with 89-148 mm³ tumors were randomized into treatmentgroups with mean tumor volumes of 121 mm³. The treatments were startedfrom the next day post randomization (defined randomization day as day0) and were treated with vehicle (50% Labrasol) or Compound 561 (62.5,125, 250, and 500 mg/kg) once a day for 28 days by oral gavage. Tumorvolumes were determined by manual calipers every 2-3 days. Mean tumorvolume and SEM are plotted. QD: once a day; PO: per oral administration.Statistical significance is calculated using two-way ANOVA followed byBonferroni post-tests in which the treatment groups were compared tovehicle control (****P<0.0001). FIG. 7A illustrates that once dailyadministration of PARP7 inhibitor Compound 561 significantly reducestumor growth in a human NCI-H1373 lung cancer xenograft. In the mouseNCI-H1373 human lung cancer cell model, Compound 561 at doses of 62.5 to500 mg/kg administered once a day for 28 days caused complete tumorregression at all dose levels.

For the CT26 study, BALB/c mice were inoculated subcutaneously in theright flank with CT26 cells for tumor development. After 5 days of cellinoculation, mice with 36-79 mm³ tumors were randomized into treatmentgroups with mean tumor volumes of 54 mm³. The treatments were startedfrom the next day post randomization (defined randomization day as day0) and were treated with vehicle (25 or 50% Labrasol) or Compound 561BID (2 times a day every 12 hours) at doses ranging from 125-500 mg/kgor QD (once a day) at 500 mg/kg for 21 days by oral gavage or needlesubcutaneously. Tumor volumes were determined by manual calipers every2-3 days. Mean tumor volume and SEM are plotted. BID: twice a day; PO:per oral administration; QD: once a day; SC: per subcutaneousadministration. The first two doses for vehicle and Compound 561 500mg/kg in the QD groups were delivered by subcutaneous injection.Statistical analysis for tumor growth inhibition (TGI) was performedwhen at least 8 of the 10 mice were remaining in the vehicle group (Day16). Statistical significance is calculated using two-way ANOVA followedby Bonferroni post-tests in which the treatment groups were compared tovehicle control (****P<0.0001). FIG. 7B illustrates that once or twicedaily administration of PARP7 inhibitor Compound 561 significantlyreduces tumor growth in a murine CT26 colon cancer syngeneic model.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

1-441. (canceled)
 442. A method of treating cancer in a patient in needof treatment comprising administering to said patient a therapeuticallyeffective amount of a compound having the structure:

or a pharmaceutically acceptable salt thereof.
 443. The method of claim442 wherein said cancer is breast cancer, cancer of the central nervoussystem, endometrium cancer, kidney cancer, large intestine cancer, lungcancer, oesophagus cancer, ovarian cancer, pancreatic cancer, prostatecancer, stomach cancer, head and neck cancer (upper aerodigestivecancer), urinary tract cancer, or colon cancer.
 444. The method of claim442 wherein said cancer is lung cancer.
 445. The method of claim 442wherein said cancer is breast cancer.
 446. The method of claim 442wherein said cancer is cancer of the central nervous system.
 447. Themethod of claim 442 wherein said cancer is endometrium cancer.
 448. Themethod of claim 442 wherein said cancer is kidney cancer.
 449. Themethod of claim 442 wherein said cancer is large intestine cancer. 450.The method of claim 442 wherein said cancer is oesophagus cancer. 451.The method of claim 442 wherein said cancer is ovarian cancer.
 452. Themethod of claim 442 wherein said cancer is pancreatic cancer.
 453. Themethod of claim 442 wherein said cancer is prostate cancer.
 454. Themethod of claim 442 wherein said cancer is stomach cancer.
 455. Themethod of claim 442 wherein said cancer is head and neck cancer (upperaerodigestive cancer).
 456. The method of claim 442 wherein said canceris urinary tract cancer.
 457. The method of claim 442 wherein saidcancer is colon cancer.
 458. A method of treating cancer in a patient inneed of treatment comprising administering to said patient atherapeutically effective amount of a compound having the structure:

or a pharmaceutically acceptable salt thereof.
 459. The method of claim448 wherein said cancer is breast cancer, cancer of the central nervoussystem, endometrium cancer, kidney cancer, large intestine cancer, lungcancer, oesophagus cancer, ovarian cancer, pancreatic cancer, prostatecancer, stomach cancer, head and neck cancer (upper aerodigestivecancer), urinary tract cancer, or colon cancer.
 460. The method of claim458 wherein said cancer is lung cancer.
 461. The method of claim 458wherein said cancer is breast cancer.
 462. The method of claim 458wherein said cancer is cancer of the central nervous system.
 463. Themethod of claim 458 wherein said cancer is endometrium cancer.
 464. Themethod of claim 458 wherein said cancer is kidney cancer.
 465. Themethod of claim 458 wherein said cancer is large intestine cancer. 466.The method of claim 458 wherein said cancer is oesophagus cancer. 467.The method of claim 458 wherein said cancer is ovarian cancer.
 468. Themethod of claim 458 wherein said cancer is pancreatic cancer.
 469. Themethod of claim 458 wherein said cancer is prostate cancer.
 470. Themethod of claim 458 wherein said cancer is stomach cancer.
 471. Themethod of claim 458 wherein said cancer is head and neck cancer (upperaerodigestive cancer).
 472. The method of claim 458 wherein said canceris urinary tract cancer.
 473. The method of claim 458 wherein saidcancer is colon cancer.